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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Aceclidine
Aceclidine
WeightAverage: 169.224
Monoisotopic: 169.110278727
Chemical FormulaC9H15NO2
CAS 827-61-2, 3-Acetoxyquinuclidine, 3-Quinuclidinol acetate (ester), Aceclidina, 0578K3ELIO
APROVAL 7/31/2025, Vizz. To treat presbyopia
1-azabicyclo[2.2.2]octan-3-yl acetate
Acetic acid 1-aza-bicyclo[2.2.2]oct-3-yl ester(aceclidine)
MW: 169.22 MF: C9H15NO2
LD50: 78 mg/kg (M, i.p.); 36 mg/kg (M, i.v.); 165 mg/kg (M, p.o.); 102 mg/kg (M, s.c.);
45 mg/kg (R, i.v.); 225 mg/kg (R, s.c.)
CN: 1-azabicyclo[2.2.2]octan-3-ol acetate (ester)
WeightAverage: 205.68
Monoisotopic: 205.0869565
Chemical FormulaC9H16ClNO2
LD50: 27 mg/kg (M, i.v.); 165 mg/kg (M, p.o.);
45 mg/kg (R, i.v.)
Aceclidine (Glaucostat, Glaunorm, Glaudin, Vizz) is a parasympathomimetic miotic agent used in the treatment of narrow angle glaucoma.
Aceclidine was approved for medical use in the United States in July 2025.[2]
Medicinal properties
Aceclidine decreases intraocular pressure. It acts as a muscarinic acetylcholine receptor agonist.[3]
Chemistry
Aceclidine is an organic compound that is structurally related to quinuclidine. As such its alternative name is 3-acetoxyquinuclidine. Its protonated derivative has a pKa of 9.3.[4]
SYN
E. E. Mikhlina and M. V. Rubtsov, Zhur. Obschei
Khim, 30, 163 (1960). L. H. Sternbach and S. Kaiser, J. Am. Chem. Soc., 74, 2215 (1952). C. A. Grob, A. Kaiser and E. Renk, Helv. Chim.Acta, 40, 2170 (1957).
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References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/218585s000lbl.pdf
- “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 4 August 2025. Retrieved 5 August 2025.
- Shannon HE, Hart JC, Bymaster FP, Calligaro DO, DeLapp NW, Mitch CH, et al. (August 1999). “Muscarinic receptor agonists, like dopamine receptor antagonist antipsychotics, inhibit conditioned avoidance response in rats”. The Journal of Pharmacology and Experimental Therapeutics. 290 (2): 901–907. doi:10.1016/S0022-3565(24)34979-1. PMID 10411607.
- Aggarwal VK, Emme I, Fulford SY (February 2003). “Correlation between pK(a) and reactivity of quinuclidine-based catalysts in the Baylis-Hillman reaction: discovery of quinuclidine as optimum catalyst leading to substantial enhancement of scope”. The Journal of Organic Chemistry. 68 (3): 692–700. doi:10.1021/jo026671s. PMID 12558387.
External links
- Clinical trial number (NCT05656027 for “Phase 3 Evaluation of the Safety and Efficacy of LNZ101 for the Treatment of Presbyopia (CLARITY)” at ClinicalTrials.gov
- Clinical trial number (NCT05728944 for “Phase 3 Efficacy Study of LNZ101 for the Treatment of Presbyopia (CLARITY)” at ClinicalTrials.gov
- Clinical trial number (NCT05753189 for “Phase 3 Safety Study for the Treatment of Presbyopia Subjects” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Other names | LNZ101 |
| AHFS/Drugs.com | Vizz |
| License data | US DailyMed: Aceclidine |
| Routes of administration | Topical (ophthalmic solution) |
| ATC code | S01EB08 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1]In general: ℞ (Prescription only) |
| Identifiers | |
| IUPAC name | |
| CAS Number | 827-61-2 6109-70-2 |
| PubChem CID | 1979 |
| ChemSpider | 1902 |
| UNII | 0578K3ELIO |
| KEGG | D02750 |
| ChEMBL | ChEMBL20835 |
| CompTox Dashboard (EPA) | DTXSID2045658 |
| ECHA InfoCard | 100.011.431 |
| Chemical and physical data | |
| Formula | C9H15NO2 |
| Molar mass | 169.224 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
///////////Aceclidine, APPROVALS 2025, FDA 2025, Vizz. To treat presbyopia, 827-61-2, 3-Acetoxyquinuclidine, 3-Quinuclidinol acetate (ester), Aceclidina, 0578K3ELIO, Glaucostat
Sepiapterin
Sepiapterin
- Sepiapterine
- CNSA-001
- CJQ26KO7HP
| Molecular Weight | 237.22 |
|---|---|
| Formula | C9H11N5O3 |
2-amino-6-[(2S)-2-hydroxypropanoyl]-7,8-dihydro-3H-pteridin-4-one
(S)-2-Amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one
- 1-(2-amino-7,8-dihydro-4-hydroxy-6-pteridinyl)-2-hydroxy-1-Propanone
- 2-amino-6-[(2S)-2-hydroxypropanoyl]-7,8-dihydropteridin-4(1H)-one
- 2-amino-7,8-dihydro-6-[(2S)-2-hydroxy-1-oxopropyl]-4(1H)Pteridinone
- S(-)-2-Amino-7,8-dihydro-6-(2-hydroxy-1-oxopropyl)-4(1H)-pteridione
- S-(-)-2-Amino-7,8-dihydro-6-(2-hydroxy-1-oxopropyl)-4(1H)-pteridinone
- 2-AMINO-7,8-DIHYDRO-6-((2S)-2-HYDROXY-1-OXOPROPYL)-4(3H)-PTERIDINONE
- 4(1H)-Pteridinone, 2-amino-7,8-dihydro-6-(2-hydroxy-1-oxopropyl)-, (S)-
7/28/2025 fda approved, Sephience, To treat hyperphenylalaninemia in patients with sepiapterin-responsive phenylketonuria, in conjunction with a phenylalanine-restricted diet
Sepiapterin, sold under the brand name Sephience, is a medication used for the treatment of hyperphenylalaninemia.[2][3] Sepiapterin is a phenylalanine hydroxylase activator.[1]
The most common side effects are upper respiratory tract infection, headache, diarrhea, abdominal pain, hyperphenylalaninemia and discoloration of feces.[2]
Syn
https://patents.google.com/patent/WO2013168693A1/en
Sepiapterin is synthesized by a method of reacting 7,8-dihydropterin and α-keto-β-hydroxybutyric acid in the presence of zinc chloride (Non-patent Document 1), and a method of oxidizing BH4 in air for 6 days. (Non-Patent Document 2) is known.
As a method for synthesizing lactoylpterin, it is known that it can be obtained by oxidizing sepiapterin (Non-patent Documents 3 and 4).International Publication No. 2011/132435
However, the method described in Non-Patent Document 1 produces only a trace amount of sepiapterin and cannot be a stable supply method. Further, in the method of Non-Patent Document 2, very expensive BH4 is used as a raw material, and this cannot be a method that can be industrially stably supplied. Further, the method of Non-Patent Document 2 has a problem that the reaction time is long and many by-products such as biopterin in which BH4 is oxidized and deoxysepiapterin from which the β-position hydroxyl group of the side chain is eliminated are also generated. . In addition, the methods for synthesizing lactoylpterin of Non-Patent Documents 3 and 4 use sepiapterin, which is difficult to obtain industrially, as a raw material, and the yield is low, which cannot be a stable supply method.
Accordingly, an object of the present invention is to provide a novel production method capable of stably supplying sepiapterin, lactoylpterin and tetrahydrolactoylpterin, which have recently been found to be useful as pharmaceuticals.
Therefore, the present inventor has studied a method for synthesizing sepiapterin, lactoylpterin, and tetrahydrolactoylpterin using available raw materials. As a starting material, the compound of the following formula (1) or the compound of formula (7) is used. As a result, it was found that sepiapterin, lactoylpterin and tetrahydrolactoylpterin can be obtained in good yield, and these compounds can be stably supplied as a medicine for the first time, thereby completing the present invention.
Example 1
Synthesis of S-lactoylpterin (2)
1- (2-Amino-4-cyclohexyloxypteridin-6-yl) -2S-methoxymethoxypropan-1-one (compound (1)) 24.7 g (68.2 mmol) in methanol 50 mL, 3 mol / L hydrochloric acid 250 mL And stirred at 50 ° C. for 3 hours. The reaction solution was adjusted to pH = 7 with an aqueous sodium hydroxide solution, collected by filtration, and dried under reduced pressure to obtain 15.1 g (64.2 mmol, 94% yield) of S-lactoylpterin.
(S-lactoylpterin: (2))
1 H NMR (DMSO-d 6 ): δ / ppm = 1.32 (d, 3H, J = 6.8Hz), 5.16 (br, 1H), 5.32 (q, 1H, J = 6.8Hz), 9.09 (s, 1H )
Example 2 (Synthesis of 1- (2-amino-4-cyclohexyloxypteridin-6-yl) -2S-hydroxypropan-1-one)
1- (2-Amino-4-cyclohexyloxypteridin-6-yl) -2St-butyldimethylsilanoxypropan-1-one (compound (1)) (4.0 g, 9.27 mmol) was added to THF 40 mL, 70% 6.92 g (18.5 mmol) of tetrabutylammonium fluoride was added and stirred at 10 ° C. or lower for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dehydrated and concentrated under reduced pressure. The crude product was purified by flash chromatography to give 2.09 g (6.59 mmol, 71% yield) of 1- (2-amino-4-cyclohexyloxypteridin-6-yl) -2S-hydroxypropan-1-one. Got.
1 H NMR (DMSO-d 6 ): δ / ppm = 1.38 (d, 3H, J = 6.6Hz), 1.37-1.79 (m, 8H), 1.98-1.99 (m, 2H), 5.20 (d, 1H, J = 6.3Hz), 5.34 (dq, 1H, J = 6.6Hz), 5.29-5.37 (m, 1H), 7.68 (br, 1H), 7.82 (br, 1H), 9.22 (s, 1H)
Example 3
Synthesis of S-lactoylpterin hydrochloride
To 500 mg (2.13 mmol) of S-lactoylpterin were added 1.25 mL of 6 mol / L hydrochloric acid and 10 mL of ethanol, and the mixture was stirred for 30 minutes. The crystals were collected by filtration and dried under reduced pressure, and 465 mg of S-lactoylpterin hydrochloride (1. 71 mmol, yield 80%).
(S-lactoylpterin hydrochloride)
1 H NMR (DMSO-d 6 ): δ / ppm = 1.34 (d, 3H, J = 6.9Hz), 3.91 (br, 3H), 5.34 (q, 1H, J = 6.9Hz), 9.12 (s, 1H )
Example 4 Synthesis of 2-amino-6- (2S-hydroxypropionyl) -7,8-dihydro-3H-pteridin-4-one (S-sepiapterin)
To 500 mg (2.13 mol) of S-lactoylpterin were added 125 mL of methanol, 2.08 mL (14.9 mmol) of triethylamine, 250 mg of 8.4% Pd / C (Ph 2 S) (containing 50% water), and an external temperature of 40 ° C. The hydrogenation reaction was carried out for 3 hours. After completion of the reaction, the reaction solution was stirred in air at room temperature for 1 hour, and then the catalyst was filtered off from the reaction solution and concentrated under reduced pressure. The crude product was separated and purified by flash chromatography and 296 mg (1.25 mmol) of S-sepiapterin. Yield 59%).
(S-sepiapterin: (3))
1 H NMR (DMSO-d 6 ): δ / ppm = 1.21 (d, 3H, J = 6.6Hz), 4.11 (s, 2H), 4.89 (d, 1H, J = 6.6Hz), 5, 10 (quin ., 1H, J = 6.6Hz), 6.81 (br-s, 2H), 7.51 (s, 1H), 10.26 (s, 1H)
Example 5
To 20 mg (0.085 mmol) of S-lactoylpterin were added 2 mL of saturated aqueous sodium hydrogen carbonate and 76 mg (0.44 mmol) of sodium dithionite, and the mixture was stirred at room temperature for 2 hours to give S-sepiapterin as a mixture.
Example 6
A reaction was carried out in the same manner as in Example 5 except that 20% (0.085 mmol) of S-lactoylpterin was used and the saturated aqueous sodium bicarbonate solution was changed to an aqueous sodium borate solution to give S-sepiapterin as a mixture.
Example 7
Synthesis of S-sepiapterin hydrochloride
To 620 mg (2.61 mmol) of S-sepiapterin were added 2.5 mL of 6 mol / L hydrochloric acid and 5.0 mL of ethanol, and the mixture was stirred at 0 ° C. for 30 minutes. The crystals were collected by filtration and dried under reduced pressure to obtain 650 mg (2.38 mmol, yield 91%) of S-sepiapterin hydrochloride.
(S-sepiapterin hydrochloride)
1 H NMR (DMSO-d 6 ): δ / ppm = 1.22 (d, 3H, J = 6.9Hz), 4.14 (s, 2H), 4.89 (d, 1H, J = 6.6Hz), 5.11 (q, 1H , J = 6.9Hz), 7.40 (br-s, 4H), 7.80 (br-s, 1H)
Example 8 (Synthesis of 2-amino-6- (2S-hydroxypropionyl) -5,6,7,8-tetrahydro-3H-pteridin-4-one (S-tetrahydrolactoylpterin) dihydrochloride)
Methanol 50 mL, 6 mol / L hydrochloric acid 5 mL, and borane pyridine complex 593 mg (6.38 mmol) were added to 1.00 g (4.25 mmol) of S-lactoylpterin, and the mixture was stirred at an external temperature of 0 ° C. for 1 hour. After completion of the reaction, 5 mL of acetone was added, concentrated under reduced pressure, azeotropically dehydrated with ethanol, ethanol was added, the crystals were filtered and dried under reduced pressure, and a mixture 1 of S-tetrahydrolactoylpterin dihydrochloride (4a) and (4b) 1 .12 g (3.59 mmol, 85% yield) was obtained.
(6S—S-tetrahydrolactoylpterin dihydrochloride: (4a))
1 H NMR (DMSO-d 6 ): δ / ppm = 1.24 (d, 3H, J = 6.9Hz), 3.45 (dd, 1H, J = 7.2, 13.5Hz), 3.87 (dd, 1H, J = 3.3, 13.5Hz), 4.34 (q, 1H, J = 6.9Hz), 4.53 (dd, 1H, J = 3.3, 7.2Hz), 7.03 (br-s, 4H), 7.67 (br-s, 1H)
(6R-S-tetrahydrolactoylpterin dihydrochloride: (4b))
1 H NMR (DMSO-d 6 ): δ / ppm = 1.24 (d, 3H, J = 6.9Hz), 3.45 (dd, 1H, J = 6.9, 13.5Hz), 3.91 (dd, 1H, J = 3.3, 13.5Hz), 4.31 (q, 1H, J = 6.6Hz), 4.55 (dd, 1H, J = 3.3, 6.9Hz), 7.12 (br-s, 3H), 7.71 (br-s, 2H)
Example 9
To 3.00 g (12.8 mmol) of S-lactoylpterin was added 150 mL of methanol, 15 mL of 6 mol / L hydrochloric acid, and 1.78 g (19.1 mmol) of borane pyridine complex, and the mixture was stirred at an external temperature of 0 ° C. for 1 hour. After completion of the reaction, 45 mL of concentrated hydrochloric acid was added, and the mixture was stirred overnight at the same temperature. The crystals were collected by filtration and dried under reduced pressure, and 1.63 g (5.2 mmol, yield) of 6S-S-tetrahydrolactoylpterin dihydrochloride (4a) 41%). The filtrate was concentrated under reduced pressure, azeotropically dehydrated with ethanol, ethanol was added, the crystals were collected by filtration and dried under reduced pressure, and 1.38 g (4.4 mmol) of 6R-S-tetrahydrolactoylpterin dihydrochloride (4b) was collected. Yield 35%). It was confirmed that the obtained compound was consistent with the spectrum data described in Example 8.
Example 10
Methanol 5 mL, 6 mol / L hydrochloric acid 0.5 mL, and borane pyridine complex 59 mg (0.64 mmol) were added to 100 mg (0.43 mmol) of S-lactoylpterin, and the mixture was stirred overnight at an external temperature of 0 ° C. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain 46 mg (0.15 mmol, yield 35%) of 6S—S-tetrahydrolactoylpterin dihydrochloride (4a). It was confirmed that the obtained compound was consistent with the spectrum data described in Example 8.
Example 11
To 200 mg (0.85 mol) of S-lactoylpterin, 50 mL of methanol, 0.62 mL (5.95 mmol) of diethylamine and 100 mg of 8.4% Pd / C (Ph 2 S) (containing 50% water) were added, and the external temperature was 40 ° C. The hydrogenation reaction was carried out for 2.5 hours. After completion of the reaction, concentrated hydrochloric acid is added, the catalyst is filtered off, concentrated under reduced pressure, azeotropically dehydrated with ethanol, ethanol is added, the crystals are filtered and dried under reduced pressure, and S-tetrahydrolactoylpterin dihydrochloride (4a) and 122 mg (0.39 mmol, 46% yield) of a mixture of (4b) was obtained. It was confirmed that the obtained compound was consistent with the spectrum data described in Example 8.
Example 12 (Synthesis of 2-amino-6- (2S-hydroxypropionyl) -5,6,7,8-tetrahydro-3H-pteridin-4-one (S-tetrahydrolactoylpterin) ditoluenesulfonate)
To 100 mg (0.43 mmol) of S-lactoylpterin was added 5 mL of methanol, 0.5 mL of water, 566 mg (2.98 mmol) of p-toluenesulfonic acid monohydrate, and 59 mg (0.64 mmol) of borane pyridine complex. Stir at 0 ° C. for 1 hour. After completion of the reaction, 0.5 mL of acetone was added and concentrated under reduced pressure. After azeotropic dehydration with ethanol, acetone was added, the crystals were collected by filtration and dried under reduced pressure, and S-tetrahydrolactoylpterin ditoluenesulfonate 158 mg (0.27 mmol, Yield 63%) was obtained.
(S-tetrahydrolactoylpterin ditoluenesulfonate)
1 H NMR (DMSO-d 6 ): δ / ppm = 1.25 (d, 3H, J = 7.2Hz), 2.29 (S, 6H), 3.35 (dd, 1H, J = 7.5, 13.5Hz), 3.84 (dd , 1H, J = 3.0, 13.5Hz), 4.35 (q, 1H, J = 6.9Hz), 4.49 (dd, 1H, J = 3.0, 7.5Hz), 6.72 (br-s, 2H), 7.13 (d, 4H, J = 8.1Hz), 7.49 (d, 4H, J = 8.1Hz), 7.62 (br-s, 1H), 10.66 (br-s, 1H)
1 H NMR (DMSO-d 6 ): δ / ppm = 1.25 (d, 3H, J = 7.2Hz), 2.29 (S, 6H), 3.33 (dd, 1H, J = 7.5, 13.5Hz), 3.84 (dd , 1H, J = 3.0, 13.5Hz), 4.32 (q, 1H, J = 6.9Hz), 4.49 (dd, 1H, J = 3.0, 7.5Hz), 6.72 (br-s, 2H), 7.13 (d, 4H, J = 8.1Hz), 7.49 (d, 4H, J = 8.1Hz), 7.62 (br-s, 1H), 10.66 (br-s, 1H)
Example 13 Synthesis of 2-amino-6- (2S-hydroxypropionyl) -7,8-dihydro-3H-pteridin-4-one (S-sepiapterin)
6 mL of water and 6 mL of ethanol were added to 1.00 g (3.20 mmol) of S-tetrahydrolactoylpterin dihydrochloride, and 363 mg (3.20 mmol) of 30% aqueous hydrogen peroxide was added at an external temperature of −10 ° C. at the same temperature. Stir for 2 hours. A sodium sulfite aqueous solution was added to the reaction solution, and the crystals were collected by filtration and dried under reduced pressure to obtain 676 mg (2.85 mmol, yield 89%) of S-sepiapterin. It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 14
46 mg of S-sepiapterin was prepared in the same manner as in Example 13 except that 100 mg (0.32 mmol) of S-tetrahydrolactoylpterin dihydrochloride was changed to 68 mg (0.32 mmol) of 36% peracetic acid with 30% hydrogen peroxide. 0.19 mmol, 61% yield). It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 15
S-Sepia was prepared in the same manner as in Example 13 except that 100 mg (0.32 mmol) of S-tetrahydrolactoylpterin dihydrochloride was changed to 85 mg of m-CPBA (content 65%, 0.32 mmol) with 30% hydrogen peroxide. 35 mg (0.15 mmol, 46% yield) of pterin was obtained. It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 16
20 mL of methanol and 0.89 mL (6.40 mmol) of triethylamine were added to 200 mg (0.64 mmol) of S-tetrahydrolactoylpterin dihydrochloride, and the mixture was stirred at room temperature for 1 hour in air. The reaction mixture was concentrated under reduced pressure, water was added, the crystals were collected by filtration and dried under reduced pressure to obtain 105 mg (0.44 mmol, yield 69%) of S-sepiapterin. It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 17
Add 20 mL of methanol to 200 mg (0.64 mmol) of S-tetrahydrolactoylpterin dihydrochloride, neutralize with 0.16 mL (1.28 mmol) of 8 mol / L aqueous sodium hydroxide solution, and stir in air at room temperature for 1 hour did. The reaction mixture was concentrated under reduced pressure, water was added, the crystals were collected by filtration and dried under reduced pressure to obtain 87 mg (0.37 mmol, yield 58%) of S-sepiapterin. It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 18 (Synthesis of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxymethoxypropan-1-one)
1- (2-Amino-4-cyclohexyloxypteridin-6-yl) -2S-methoxymethoxypropan-1-one (1.00 g, 2.77 mmol), ethyl acetate 60 mL, 10% Pd—C 500 mg, potassium carbonate 3 .82 g (27.6 mmol) was added, and the hydrogenation reaction was performed at an external temperature of 50 ° C. for 3 hours. After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure. The crude product was separated and purified by flash chromatography to obtain 257 mg (0.71 mmol) of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxymethoxypropan-1-one. Yield 26%).
1 H NMR (CDCl 3 ): δ / ppm = 1.33-1.47 (m, 3H), 1.44 (d, 3H, J = 6.9Hz), 1.54-1.63 (m, 3H), 1.79 (m, 2H), 1.91 (m, 2H), 3.37 (s, 3H), 4.36 (d, 1H, J = 15.6), 4.43 (d, 1H, J = 15.6), 4.71 (d, 1H, J = 6.6Hz), 4.74 (d , 1H, J = 6.6Hz), 4.90 (br-s, 2H), 5.00 (br-s, 1H), 5.05-5.11 (m, 1H), 5.34 (q, 1H, J = 6.9Hz)
Example 19 (Synthesis of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxyethoxymethoxypropan-1-one)
100 mg (0.56 mmol) of ascorbic acid was weighed and 2 mL of water was added. 1- (2-amino-4-cyclohexyloxypteridin-6-yl) -2S-methoxyethoxymethoxypropane- dissolved in 2 mL of methanol after neutralizing the pH of the solution with 1 mol / L aqueous sodium hydroxide solution 20 mg (0.054 mmol) of 1-one was added. To this, 80 mg (0.46 mmol) of Na 2 S 2 O 4 was added and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. After dehydrating the organic phase, the solvent was concentrated under reduced pressure. Separation and purification by silica gel column chromatography gave 4.4 mg (0.011 mmol) of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxyethoxymethoxypropan-1-one. Yield 20%).
1 H NMR (CDCl 3 ): δ / ppm = 1.13 (m, 1H), 1.44 (d, 3H, J = 6.8 Hz), 1.63 (m, 1H), 1.80 (m, 2H), 1.93 (m, 2H ), 2.06 (m, 2H), 3.37 (s, 3H), 3.52 (m, 2H), 3.70 (t, J = 4.6 Hz, 2H), 4.40 (m, 2H), 4.81 (m, 2H), 5.11 (tt, J = 3.9, 8.5 Hz, 1H), 5.35 (q, J = 6.8 Hz, 1H)
Example 20
Synthesis of S-sepiapterin (3)
To 10 mg of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxymethoxypropan-1-one (compound (5-2)) was added 0.1 mL of concentrated hydrochloric acid. , Warmed up. The reaction solution was diluted with water, neutralized to pH 6-7 with an aqueous sodium hydroxide solution, and the precipitated crystals were filtered off. The filtrate was concentrated under reduced pressure to obtain S-sepiapterin as a mixture. The resulting compound was consistent with the spectral data described in Example 4.
Example 21
Synthesis of S-sepiapterin (3)
4.0 mg (9.8 μmol) of 1- (2-amino-4-cyclohexyloxy-7,8-dihydropteridin-6-yl) -2S-methoxyethoxymethoxypropan-1-one in 2 mL of methanol, ascorbic acid 3 0.02 mg was added, 2 mL of 3 mol / L hydrochloric acid was added thereto, and the mixture was stirred at 50 ° C. for 6 hours while shielding light. The solution was adjusted to pH 7 with 28% aqueous ammonia, washed with ethyl acetate, and purified by Florisil column chromatography to obtain 2.0 mg (8.4 μmol, yield 86%) of S-sepiapterin. As a result of HPLC measurement, the retention time and the UV waveform of the peak coincided with the standard S-sepiapterin.
Example 22 (Synthesis of 2-amino-6- [2S- (tert-butyldimethylsilanyloxy) -propionyl] -3H-pteridin-4-one (6))
To 3.00 g (12.8 mmol) of S-lactoylpterin were added 30 mL of DMF, 2.61 g (38.3 mmol) of imidazole and 3.84 g (25.5 mmol) of TBSCl, and the mixture was stirred for 1 hour under ice cooling. Water was added to the reaction mixture, and the crystals were collected by filtration and dried under reduced pressure to give 3.91 g of 2-amino-6- [2S- (tert-butyldimethylsilanyloxy) -propionyl] -3H-pteridin-4-one (6). (11.2 mmol, 88% yield) was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 0.01 (s, 3H), 0.06 (s, 3H), 0.83 (s, 9H), 1.36 (d, 3H, J = 6.9Hz), 5.55 (q , 1H, J = 6.9Hz), 9.10 (s, 1H), 11.73 (br-s, 1H)
Example 23 (Synthesis of 2-amino-6- [2S- (triisopropylsilanyl) -propionyl] -3H-pteridin-4-one (6))
2-amino-6- [2S- (triisopropylsilanyl) -propionyl] -3H- was prepared in the same manner as in Example 22 except that TBSCl was changed to TIPSCl from 300 mg (1.28 mmol) of S-lactoylpterin. Pteridin-4-one (6) (339 mg, 0.87 mmol, yield 68%) was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 0.89-1.15 (m, 21H), 1.40 (d, 3H, J = 6.9Hz), 5.71 (q, 1H, J = 6.9Hz), 9.13 (s , 1H), 11.74 (br-s, 1H)
Example 24 (Synthesis of 2-amino-6- [2S- (tert-butyldiphenylsilanyl) -propionyl] -3H-pteridin-4-one (6))
2-amino-6- [2S- (triisopropylsilanyl) -propionyl] -3H- was prepared in the same manner as in Example 22 except that TBSCl was changed to TBDPSCl from 300 mg (1.28 mmol) of S-lactoylpterin. 498 mg (1.05 mmol, yield 82%) of pteridin-4-one (6) was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 1.03 (s, 9H), 1.38 (d, 3H, J = 6.9Hz), 5.71 (q, 1H, J = 6.9Hz), 7.23-7.33 (m , 3H), 7.37-7.45 (m, 3H), 7.50-7.59 (m, 2H), 7.61-7.71 (m, 2H), 8.96 (s, 1H), 11.67 (br-s, 1H)
Example 25 (1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one Synthesis of (7))
2-amino-6- [2S- (tert-butyldimethylsilanyloxy) -propionyl] -3H-pteridin-4-one 1.50 g (4.29 mmol) and 75 mL of ethyl acetate, di-tert-butyl dicarbonate 4 .68 g (21.4 mmol) and N, N-dimethylaminopyridine 52 mg (0.43 mmol) were added, and the mixture was heated to reflux for 1 hour. The reaction solution is washed with water, and the organic layer is dehydrated and concentrated under reduced pressure to give 2- (N, N-di-tert-butylcarbonyl) -amino-6- [2S- (tert-butyldimethylsilanyloxy) -propionyl]- 2.18 g (3.35 mmol, yield 78%) of 3H-pteridin-4-one (7) was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 0.01 (s, 3H), 0.08 (s, 3H), 0.75 (s, 9H), 1.40 (d, 3H, J = 6.6Hz), 1.48 (s , 18H), 1.71 (s, 9H), 5.59 (q, 1H, J = 6.6Hz), 9.53 (s, 1H)
Example 26 (1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butoxycarbonyloxypropan-1-one (7 )
To 1.00 g (4.25 mmol) of S-lactoylpterin was added 50 mL of THF, 4.64 g (21.3 mmol) of di-tert-butyl dicarbonate, and 30 mg (0.25 mmol) of N, N-dimethylaminopyridine. Heated to reflux for hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography, and 1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] There was obtained 0.30 g (0.47 mmol, yield 11%) of -2S-tert-butoxycarbonyloxypropan-1-one (7).
1 H NMR (CDCl 3 ): δ / ppm = 1.26 (s, 9H), 1.27 (d, 3H, J = 7.2Hz), 1.45 (s, 18H), 1.71 (s, 9H), 6.11 (q, 1H , J = 7.2Hz), 6.73 (s, 1H)
Example 27 (Synthesis of 1- [4-cyclohexyloxy-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-methoxymethoxypropan-1-one)
1- (2-Amino-4-cyclohexyloxypteridin-6-yl) -2S-methoxymethoxypropan-1-one (1.00 g, 2.76 mmol) was added with 20 mL of THF and 1.27 g of di-tert-butyl dicarbonate ( 5.82 mmol) and 3.4 mg (0.03 mmol) of N, N-dimethylaminopyridine were added, and the mixture was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure to give 1- [4-cyclohexyloxy-2- (N, N-di-tert-butylcarbonyl) aminopteridin-6-yl] -2S-methoxymethoxypropan-1-one (7) 1 Obtained .55 g (2.76 mmol, 100% yield).
1 H NMR (DMSO-d 6 ): δ / ppm = 1.45-1.88 (m, 8H), 1.53 (s, 18H), 1.58 (d, 3H, J = 6.9Hz), 2.10-2.14 (m, 2H) , 3.38 (s, 3H), 4.78 (d, 1H, J = 6.9Hz), 4.84 (d, 1H, J = 6.9Hz), 5.36-5.45 (m, 1H), 5.55 (q, 1H, J = 6.9 Hz), 9.65 (s, 1H)
Example 28 (1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-7,8-dihydropteridin-6-yl] -2S-tert-butyldimethylsilanyl Synthesis of oxypropan-1-one)
1- [4-tert-Butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one 1.31 g ( 2.02 mmol) was added with 130 mL of ethyl acetate, 655 mg of 10% Pd—C and 2.78 g (20.1 mmol) of potassium carbonate, and the hydrogenation reaction was carried out for 1 hour at an external temperature of 50 ° C. under normal pressure (H 2 balloon). . After the catalyst was filtered off, the reaction solution was stirred in air at room temperature overnight, and the reaction solution was concentrated under reduced pressure. The crude product was separated and purified by flash chromatography, and 1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-7,8-dihydropteridin-6-yl]- 684 mg (1.05 mmol, 66% yield) of 2S-tert-butyldimethylsilanyloxypropan-1-one was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 0.01 (s, 3H), 0.07 (s, 3H), 0.82 (s, 9H), 1.24 (d, 3H, J = 6.6Hz), 1.42 (s , 18H), 1.53 (s, 9H), 4.23 (d, 1H, J = 16.5Hz), 4.32 (d, 1H, J = 16.5Hz), 5.39 (q, 1H, J = 6.6Hz), 7.92 (s , 1H)
Example 29 (Synthesis of 2-amino-6S- (2S-hydroxypropionyl) -5,6,7,8-tetrahydro-3H-pteridin-4-one (6S-S-tetrahydrolactoylpterin) dihydrochloride)
1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one 4.92 g ( 7.57 mmol) was added 250 mL of ethyl acetate, 2.46 g of 10% Pd—C, and 10.5 g (76.0 mmol) of K 2 CO 3 , and the hydrogenation reaction was performed at an external temperature of 50 ° C. under normal pressure (H 2 balloon). It went for 1 hour. After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure, 49 mL of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. Ethanol was added to the concentrate, and the crystals were collected by filtration and dried under reduced pressure to obtain 1.79 g (5.73 mmol, yield 76%) of 6S—S-tetrahydrolactoylpterin dihydrochloride (4a). The compound obtained agreed with the spectral data described in Example 8.
Example 30
1- [4-tert-Butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one 500 mg (0. 164 mg (0.53 mmol, 68% yield) of 6S—S-tetrahydrolactoylpterin dihydrochloride (4a) was obtained in the same manner as in Example 29 except that the amount of 10% Pd / C was changed to 100 mg from 77 mmol). Obtained. It was confirmed that the obtained compound was consistent with the spectrum data described in Example 8.
Example 31 (1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-5,6,7,8-tetrahydropteridin-6-yl] -2S-tert- Synthesis of butyldimethylsilanyloxypropan-1-one)
1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one 100 mg (0. 15 mmol), 10 mL of ethyl acetate, 20 mg of 10% Pd—C and 156 mg (1.54 mmol) of triethylamine were added, and the hydrogenation reaction was carried out for 1 hour at an external temperature of 50 ° C. under normal pressure (H 2 balloon). After the catalyst was filtered off, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography to give 1- [4-tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino. -5,6,7,8-tetrahydropteridin-6S-yl] -2S-tert-butyldimethylsilanyloxypropan-1-one (8a) 30 mg (0.045 mmol, 30% yield) and 1- [4 -Tert-butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-5,6,7,8-tetrahydropteridin-6R-yl] -2S-tert-butyldimethylsilanyloxypropane-1 -30 mg (0.045 mmol, 30% yield) of ONE (8b) was obtained.
(8a)
1 H NMR (DMSO-d 6 ): δ / ppm = 0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 1.21 (d, 3H, J = 6.6Hz), 1.37 (s , 18H), 1.49 (s, 9H), 3.56-3.67 (m, 2H), 4.39 (m, 1H), 4.42 (q, 1H, J = 6.6Hz), 4.79 (s, 1H), 7.00 (s, 1H)
(8b)
1 H NMR (DMSO-d 6 ): δ / ppm = 0.08 (s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 1.23 (d, 3H, J = 6.6Hz), 1.37 (s , 18H), 1.49 (s, 9H), 3.40-3.53 (m, 2H), 4.35 (m, 1H), 4.44 (q, 1H, J = 6.6Hz), 4.93 (s, 1H), 7.09 (s, 1H)
Example 32 (1- [4-cyclohexyloxy-2- (N, N-di-tert-butoxycarbonyl) amino-5,6,7,8-tetrahydropteridin-6-yl] -2S-methoxymethoxypropane- Synthesis of 1-one)
From Example 1 from 200 mg (0.36 mmol) of 1- [4-cyclohexyloxy-2- (N, N-di-tert-butoxycarbonyl) aminopteridin-6-yl] -2S-methoxymethoxypropan-1-one In a similar manner, 1- [4-cyclohexyloxy-2- (N, N-di-tert-butoxycarbonyl) amino-5,6,7,8-tetrahydropteridin-6-yl] -2S-methoxymethoxypropane- 76 mg (0.13 mmol, yield = 38%) of 1-one was obtained.
1 H NMR (DMSO-d 6 ): δ / ppm = 1.21 (d, 3H, J = 6.9Hz), 1.32-1.37 (m, 3H), 1.38 (s, 18H), 1.43-1.51 (m, 3H) , 1.73 (m, 2H), 1.89-1.91 (m, 2H), 3.27 (s, 3H), 3.51-3.56 (m, 2H), 4.33-4.35 (m, 1H), 4.41 (q, 1H, J = 6.9Hz), 4.59 (d, 1H, J = 6.9Hz), 4.67 (d, 1H, J = 6.9Hz), 4.86-4.89 (m, 1H), 4.95 (d, 1H, J = 2.7Hz), 7.08 (s, 1H)
1 H NMR (DMSO-d 6 ): δ / ppm = 1.24 (d, 3H, J = 6.9Hz), 1.32-1.37 (m, 3H), 1.38 (s, 18H), 1.43-1.51 (m, 3H) , 1.73 (m, 2H), 1.89-1.91 (m, 2H), 3.32 (s, 3H), 3.51-3.56 (m, 2H), 4.33-4.35 (m, 1H), 4.39 (q, 1H, J = 6.9Hz), 4.59 (d, 1H, J = 6.9Hz), 4.67 (d, 1H, J = 6.9Hz), 4.86-4.89 (m, 1H), 5.01 (d, 1H, J = 2.4Hz), 7.08 (s, 1H)
Example 33 Synthesis of 2-amino-6- (2S-hydroxypropionyl) -7,8-dihydro-3H-pteridin-4-one (S-sepiapterin)
1- [4-tert-Butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-7,8-dihydropteridin-6-yl] -2S-tert-butyldimethylsilanyloxypropane-1 -To 300 mg (0.46 mmol) of ON was added 3 mL of acetonitrile and 6 mL of 2 mol / L hydrochloric acid, and the mixture was stirred at an external temperature of 40 ° C for 3 hours. The reaction solution was adjusted to pH = 7 with an aqueous sodium hydroxide solution, and the crystals were collected by filtration and dried under reduced pressure to obtain 96 mg (0.40 mmol, yield 88%) of S-sepiapterin. It was confirmed that the obtained compound was consistent with the spectral data described in Example 4.
Example 34 (Synthesis of 2-amino-6R- (2S-hydroxypropionyl) -5,6,7,8-tetrahydro-3H-pteridin-4-one (6R-S-tetrahydrolactoylpterin) dihydrochloride)
1- [4-tert-Butoxycarbonyl-2- (N, N-di-tert-butoxycarbonyl) amino-5,6,7,8-tetrahydropteridin-6R-yl] -2S-tert-butyldimethylsilanyl To 393 mg (0.60 mmol) of oxypropan-1-one (8b) was added 10 mL of concentrated hydrochloric acid, and the mixture was concentrated under reduced pressure. Ethanol was added to the concentrate, and the crystals were collected by filtration and dried under reduced pressure to obtain 106 mg (0.34 mmol, yield 56%) of 6R—S-tetrahydrolactoylpterin dihydrochloride (4b). The compound obtained agreed with the spectral data described in Example 8.
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Medical uses
Sepiapterin is indicated for the treatment of hyperphenylalaninemia in people with phenylketonuria.[1][2]
Side effects
The most common side effects are upper respiratory tract infection, headache, diarrhea, abdominal pain, hyperphenylalaninemia and discoloration of feces.[2]
Society and culture
Legal status
In April 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Sephience, intended for the treatment of hyperphenylalaninemia in adults and children with phenylketonuria.[2] The applicant for this medicinal product is PTC Therapeutics International Limited.[2] Sepiapterin was authorized for medical use in the European Union in June 2025.[2][3]
Sepiapterin was approved for medical use in the United States in July 2025.[1]
Research
Deficiency of tetrahydrobiopterin can cause toxic buildup of phenylalanine (phenylketonuria) as well as deficiencies of dopamine, norepinephrine, and epinephrine, leading to dystonia and other neurological illnesses. This has led to clinical study of sepiapterin in humans to treat tetrahydrobiopterin deficiency.[4]
Since atherosclerosis and other circulatory diseases associated with diabetes are also associated with tetrahydrobiopterin deficiency, animal studies of the value of sepiaterin in these vascular diseases have been done. These studies show that relaxation of the blood vessels studied was impaired after animals were given sepiapterin, even though their levels of tetrahydrobiopterin were replenished.[5]
References
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219666s000lbl.pdf
- “Sephience EPAR”. European Medicines Agency (EMA). 25 April 2025. Retrieved 2 May 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “Sephience Product information”. Union Register of medicinal products. 25 June 2025. Retrieved 27 June 2025.
- Smith N, Longo N, Levert K, Hyland K, Blau N (April 2019). “Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers”. Molecular Genetics and Metabolism. 126 (4): 406–412. doi:10.1016/j.ymgme.2019.02.001. ISSN 1096-7192. PMID 30922814. S2CID 85564348.
- Vasquez-Vivar J, Duquiane D, Whitsett J, Kalyanaraman B, Rajagopalan S (October 2002). “Altered Tetrahydrobiopterin Metabolism in Atherosclerosis”. Arteriosclerosis, Thrombosis, and Vascular Biology. 22 (10): 1655–1661. doi:10.1161/01.ATV.0000029122.79665.D9. PMID 12377745.
| Names | |
|---|---|
| IUPAC name2-amino-6-[(2S)-2-hydroxypropanoyl]-7,8-dihydro-1H-pteridin-4-one | |
| Other namesSephience | |
| Identifiers | |
| CAS Number | 17094-01-8 |
| 3D model (JSmol) | Interactive image |
| ChEMBL | ChEMBL1255653 |
| ChemSpider | 58746 |
| KEGG | C00835 |
| PubChem CID | 65253 |
| UNII | CJQ26KO7HP |
| InChI | |
| SMILES | |
| Properties | |
| Chemical formula | C9H11N5O3 |
| Molar mass | 237.22 g/mol |
| Pharmacology | |
| ATC code | None |
| Routes of administration | By mouth |
| Legal status | US: ℞-only[1]EU: Rx-only[2][3] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?)Infobox references | |
- [1]. Pannirselvam M, et al. Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br J Pharmacol. 2003;140(4):701‐706. [Content Brief][2]. Cho YR, et al. Sepiapterin inhibits cell proliferation and migration of ovarian cancer cells via down-regulation of p70S6K-dependent VEGFR-2 expression. Oncol Rep. 2011;26(4):861‐867. [Content Brief]
//////////Sepiapterin, approvals 2025, fda 2025, Sephience, Sepiapterine, CNSA 001, CJQ26KO7HP, PTC 923, WHO 11848,
Sebetralstat
Sebetralstat, KVD 900
CAS 1933514-13-6
491.5 g/mol
FDA 7/3/2025, Ekterly, To treat acute attacks of hereditary angioedema
N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-[[4-[(2-oxopyridin-1-yl)methyl]phenyl]methyl]pyrazole-4-carboxamide
Sebetralstat, sold under the brand name Ekterly, is a medication used for the treatment of hereditary angioedema.[1] Sebetralstat is a plasma kallikrein inhibitor.[1]
Sebetralstat was approved for medical use in the United States in July 2025.[1][2]
SYN
https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00921
aReagents and conditions: (a) 2-Hydroxypyridine (1.2 equiv), K2CO3 (3.0 equiv), acetone, 50 °C, 18 h, 78%; (b) methanesulfonyl chloride (1.3 equiv), Et3N, (1.4 equiv), dichloromethane, rt, 18h, 93%; (c) methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (0.83 equiv), K2CO3 (2.0 equiv), DMF, 60 °C, 18 h, 54%; (d) NaOH (3.0 equiv), THF-MeOH-H2O, rt, 18 h, 34%; (e) 22a (1.0 equiv), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (1.0 equiv), HATU (1.1 equiv), Et3N (6.0 equiv), dichloromethane, rt, 4 h, 64%.
Synthesis of Sebetralstat
1-(4-Hydroxymethyl-benzyl)-1H-pyridin-2-one (19)
4-(Chloromethyl)benzyl alcohol 18 (5.0 g, 31.9 mmol) was added to a solution of potassium carbonate (13.2 g, 96 mmol) and 2-hydroxypyridine (3.6 g, 38.3 mmol) in acetone (250 mL). The reaction mixture was heated at 50 °C for 18 h and then concentrated in vacuo. The residue was partitioned between dichloromethane (300 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 × 300 mL). The combined organic layers were washed with brine (300 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica (0–10% methanol in dichloromethane) to afford 19 (5.4 g, 25.1 mmol, 78% yield) as a white solid. MS (ESI) m/z 216.0 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 9.0, 6.6, 2.1 Hz, 1H), 7.34–7.21 (m, 4H), 6.41 (dd, J = 9.1, 1.3 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.15 (t, J = 5.7 Hz, 1H), 5.07 (s, 2H), 4.46 (d, J = 5.7 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ 161.4, 141.9, 140.0, 139.0, 135.7, 127.5, 126.6, 119.8, 105.4, 62.6, 50.8.
1-(4-Chloromethyl-benzyl)-1H-pyridin-2-one (20)
A reaction flask containing 1-(4-hydroxymethyl-benzyl)-1H-pyridin-2-one (19) (8.45 g, 39.3 mmol), dry dichloromethane (80 mL), and triethylamine (7.66 mL, 55.0 mmol) was cooled in an ice–water bath. Methanesulfonyl chloride (3.95 mL, 51.0 mmol) was added to the reaction at 0 °C, and ice–water bath cooling continued. After 15 min, the ice–water bath was removed and stirring continued at room temperature overnight. The reaction mixture was partitioned between dichloromethane (100 mL) and saturated aqueous ammonium chloride solution (100 mL). The aqueous layer was extracted with further dichloromethane (2 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford 20 (8.65 g, 36.6 mmol, 93% yield) as a pale yellow solid. MS (ESI) m/z 234.1 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.79 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.49–7.39 (m, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H), 6.42 (ddd, J = 9.2, 1.3, 0.7 Hz, 1H), 6.24 (td, J = 6.7, 1.4 Hz, 1H), 5.09 (s, 2H), 4.73 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 161.4, 140.1, 139.1, 137.6, 136.9, 129.0, 127.9, 119.9, 105.5, 50.8, 45.8.
Methyl 3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21a) and Methyl 5-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate (21b)
Methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.11 g, 11.77 mmol; CAS No. 318496-66-1) was added to a solution of potassium carbonate (3.25 g, 23.54 mmol) and 1-(4-chloromethyl-benzyl)-1H-pyridin-2-one 20 (3.30 g, 14.12 mmol) in N,N-dimethylformamide (5 mL) and heated at 70 °C for 3 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 × 100 mL), and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (120 g column, 0–100% (10% ethanol in ethyl acetate) in isohexanes to afford two regioisomers: 21a (2.03 g, 5.47 mmol, 47% yield) as an off-white solid and 21b (350 mg, 0.92 mmol, 8% yield). 21a MS (ESI) m/z 368.1 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.76 (dd, J = 6.8, 2.2 Hz, 1H), 7.41 (ddd, J = 8.9, 6.5, 2.1 Hz, 1H), 7.25 (d, J = 1.2 Hz, 4H), 6.40 (dt, J = 9.1, 1.0 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.30 (s, 2H), 5.07 (s, 2H), 4.49 (s, 2H), 3.72 (s, 3H), 3.23 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.2, 161.8, 150.5, 140.6, 139.6, 137.6, 136.3, 135.6, 128.5, 128.4, 120.3, 111.8, 106.0, 66.0, 58.0, 55.1, 51.5, 51.2. 21b MS (ESI) m/z 368.1 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.76 (dd, J = 6.8, 2.1 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.28–7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.43–6.36 (m, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.35 (s, 2H), 5.06 (s, 2H), 4.78 (s, 2H), 3.75 (s, 3H), 3.25 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 163.4, 161.8, 142.4, 140.9, 140.5, 139.6, 137.4, 136.2, 128.3, 120.3, 112.8, 106.0, 61.7, 58.2, 53.0, 51.7, 51.2.
3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid (22a)
To methyl 3-(methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylate 21a (3.77 g, 10.26 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (15.39 mL, 30.80 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was acidified with 1 M aqueous HCl solution (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 22a (1.22 g, 3.45 mmol, 34% yield) as a white solid. MS (ESI) m/z 354.2 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.32 (s, 1H), 7.76 (ddd, J = 6.8, 2.1, 0.7 Hz, 1H), 7.41 (ddd, J = 8.9, 6.6, 2.1 Hz, 1H), 7.30–7.20 (m, 4H), 6.40 (ddd, J = 9.1, 1.4, 0.7 Hz, 1H), 6.22 (td, J = 6.7, 1.4 Hz, 1H), 5.29 (s, 2H), 5.07 (s, 2H), 4.50 (s, 2H), 3.22 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.3, 161.8, 150.5, 140.6, 139.6, 137.6, 136.4, 135.6, 128.5, 128.4, 120.3, 113.0, 106.0, 66.0, 58.0, 55.1, 51.2.
3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic Acid (3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-amide (14w)
3-(Methoxymethyl)-1-(4-((2-oxopyridin-1(2H)-yl)methyl)benzyl)-1H-pyrazole-4-carboxylic acid 22a (75 mg, 0.212 mmol), C-(3-fluoro-4-methoxy-pyridin-2-yl)-methylamine (49 mg, 0.212 mmol; CAS No. 1256812-75-5), and HATU (89 mg, 0.233 mmol) were suspended in anhydrous dichloromethane (3 mL) to which triethylamine (177 μL, 1.270 mmol) was added, sonicated, and then left to stir at room temperature for 4 h. The solvent was removed under reduced pressure, and the resulting residue was quenched with saturated aqueous ammonium chloride solution (5 mL). An off-white solid resulted, which was sonicated, filtered under reduced pressure, washed with water, and dried in a vacuum oven at 40 °C overnight. The residue was purified by chromatography eluting with 1% NH3 in MeOH/dichloromethane to afford 14w as a white solid (67 mg, 64% yield). MS (ESI) m/z 492.0 (M + H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.42 (t, J = 5.4 Hz, 1H), 8.29–8.21 (m, 2H), 7.75 (ddd, J = 0.7, 2.1, 6.8 Hz, 1H), 7.41 (ddd, J = 2.1, 6.6, 8.9 Hz,1H), 7.28–7.17 (m, 5H), 6.39 (ddd, J = 0.7, 1.4, 9.2 Hz, 1H), 6.22 (td, J = 1.4, 6.7 Hz, 1H), 5.28 (s, 2H), 5.07 (s, 2H), 4.57–4.46 (m, 4H), 3.92 (s, 3H), 3.25 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 161.9, 161.3, 153.0 (JC–F = 8.7 Hz), 147.5, 146.8 (JC–F = 253.5 Hz), 146.0 (JC–F = 7.2 Hz), 145.2 (JC–F = 11.6 Hz), 140.1, 139.1, 137.1, 136.0, 133.2, 128.1, 127.9, 119.9, 116.3, 108.7, 105.5, 66.3, 57.5, 56.4, 54.6, 50.7, 38.3.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US232820883&_cid=P22-MCYEU3-92408-1
Example 41
3-Fluoro-4-methoxy-pyridine-2-carbonitrile
(3-Fluoro-4-methoxy-pyridin-2-ylmethyl)-carbamic acid tert-butyl ester
C-(3-Fluoro-4-methoxy-pyridin-2-yl)-methylamine hydrochloride salt
3-Methoxymethyl-1-[4-(2-oxo-2H-pyridin-1-ylmethyl)-benzyl]-1H-pyrazole-4-carboxylic acid (3-fluoro-4-methoxy-pyridin-2-ylmethyl)-amide
Medical uses
Sebetralstat is indicated for the treatment of acute attacks of hereditary angioedema.[1]
Pharmacology
Sebetralstat is a plasma kallikrein inhibitor that contains the unusual 2-pyridone heterocycle.[3]
Society and culture
Legal status
Sebetralstat was approved for medical use in the United States in July 2025.[1] The US Food and Drug Administration granted the application for sebetralstat orphan drug designation.[4]
Names
Sebetralstat is the international nonproprietary name.[5]
Sebetralstat is sold under the brand name Ekterly.[1]
References
- ^ Jump up to:a b c d e f g “Ekterly- sebetralstat tablet”. DailyMed. 7 July 2025. Retrieved 9 July 2025.
- ^ “KalVista Pharmaceuticals Announces FDA Approval of Ekterly (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema” (Press release). Kalvista. 7 July 2025. Retrieved 9 July 2025 – via Business Wire.
- ^ Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, et al. (October 2022). “Sebetralstat (KVD900): A Potent and Selective Small Molecule Plasma Kallikrein Inhibitor Featuring a Novel P1 Group as a Potential Oral On-Demand Treatment for Hereditary Angioedema”. Journal of Medicinal Chemistry. 65 (20): 13629–13644. doi:10.1021/acs.jmedchem.2c00921. PMC 9620001. PMID 36251573.
- ^ “Sebetralstat Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 9 July 2025.
- ^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.
External links
- “Sebetralstat (Code – C184930)”. EVS Explore.
- Clinical trial number NCT05259917 for “A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Ekterly |
| Other names | KVD-900, KVD900 |
| License data | US DailyMed: Sebetralstat |
| Routes of administration | By mouth |
| ATC code | B06AC08 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1933514-13-6 |
| PubChem CID | 121365142 |
| IUPHAR/BPS | 11947 |
| DrugBank | DB18305 |
| ChemSpider | 115006749 |
| UNII | O5ZD2TU2B7 |
| KEGG | D12396 |
| ChEMBL | ChEMBL5095248 |
| Chemical and physical data | |
| Formula | C26H26FN5O4 |
| Molar mass | 491.523 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
//////////Sebetralstat, FDA 2025, APPROVALS 2025, Ekterly, angioedema, KVD 900, O5ZD2TU2B7
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Sunvozertinib
Sunvozertinib
CAS 2370013-12-8
DZD9008, 584.1 g/mol, C29H35ClFN7O3, A-1801, L1Q2K5JYO8
N-[5-[[4-[5-chloro-4-fluoro-2-(2-hydroxypropan-2-yl)anilino]pyrimidin-2-yl]amino]-2-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-4-methoxyphenyl]prop-2-enamide
FDA Zegfrovy, 7/2/2025
To treat locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations, as detected by an FDA-approved test, with disease progression on or after platinum-based chemotherapy |
Sunvozertinib (DZD9008) is a potent ErbBs (EGFR, Her2, especially mutant forms) and BTK inhibitor. Sunvozertinib shows IC50s of 20.4, 20.4, 1.1, 7.5, and 80.4 nM for EGFR exon 20 NPH insertion, EGFR exon 20 ASV insertion, EGFR L858R and T790M mutations, and Her2 Exon20 YVMA, and EGFR WT A431, respectively (patent WO2019149164A1, example 52).
Sunvozertinib, sold under the brand name 舒沃哲, among others is an anti-cancer medication used for the treatment of non-small-cell lung cancer.[2][3] It is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor.[2][4]
Sunvozertinib was approved for medical use in the United States in July 2025.[1]
Medical uses
In the US, sunvozertinib is indicated for the treatment of adults with locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[1]
Side effects
The US FDA prescribing information for sunvozertinib includes warnings and precautions for interstitial lung disease/pneumonitis, gastrointestinal adverse reactions, dermatologic adverse reactions, ocular toxicity, and embryo-fetal toxicity.[1]
History
Sunvozertinib is being developed by Dizal Pharmaceutical.[5] In China, it was conditionally approved in 2023 for the treatment of NSCLC and full approval is contingent on results of phase 3 clinical trials.[6] In the United States, it has been designated by the Food and Drug Administration as a breakthrough therapy for patients with locally advanced or metastatic NSCLCs with an EGFR exon 20 insertion mutation.[7]
Efficacy was evaluated in WU-KONG1B (NCT03974022), a multinational, open-label, dose randomization trial.[1] Eligible participants had locally advanced or metastatic non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations with disease progression on or after platinum-based chemotherapy.[1] The primary efficacy population was in 85 participants who received sunvozertinib 200 mg orally once daily with food until disease progression or intolerable toxicity.[1]
The US Food and Drug Administration granted the application for sunvozertinib priority review and breakthrough therapy designations.[1]
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019149164&_cid=P10-MCWSEU-52423-1
[1286]
(R) -N- (5- (4- (5-chloro-4-fluoro-2- (2-hydroxypropan-2-yl) phenylamino) pyrimidin-2-ylamino) -2- (3- (dimethylamino) pyrrolidin-1-yl) -4-methoxyphenyl) acrylamide
Procedure for the preparation of compound 52a:
[1289]
To a solution of compound 36b (200 mg, 0.429 mmol) and K 2CO 3(119 mg, 0.858 mmol) in DMSO (3 mL) was added (R) -N, N-dimethylpyrrolidin-3-amine (59 mg, 0.515 mmol) . The reaction mixture was stired at 22-30℃ for 4 h, then 50℃ for 1 h while color changed from brown to deep orange. The reaction mixture was added drop wise into H 2O (40 mL) under ice water bath. The precipitated solid was collected by filtration and washed with H 2O (15 mL × 3) , the filter cake was dissolved with CH 2Cl 2(20 mL) , dried over Na 2SO 4and concentrated in vacuum to give compound 52a (210 mg, 87.4%yield) as an orange solid.
[1290]
LCMS: R t=0.677 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2mm) , MS (ESI) m/z=559.9 [M+H] +.
[1291]
1H NMR (400MHz, Methanol-d 4) δ 8.42 (s, 1H) , 7.99 (d, J=7.6 Hz, 1H) , 7.96 (d, J=5.6 Hz, 1H) , 7.24 (d, J=10.8 Hz, 1H) , 6.50 (s, 1H) , 6.15 (d, J=5.6 Hz, 1H) , 3.96 (s, 3H) , 3.54 (dt, J=6.4, 10.4 Hz, 1H) , 3.36 (t, J=9.2 Hz, 1H) , 3.28 -3.24 (m, 1H) , 3.09 (dd, J=6.8, 10.0 Hz, 1H) , 2.93 -2.81 (m, 1H) , 2.33 (s, 6H) , 2.30 -2.25 (m, 1H) , 1.97 -1.82 (m, 1H) , 1.59 (d, J=3.6 Hz, 6H) .
[1292]
Procedure for the preparation of compound 52b:
[1293]
To a solution of compound 52a (210 mg, 0.375 mmol) in 5 mL MeOH/H 2O=5/1 (v/v) was added Zn (147 mg, 2.25 mmol) and NH 4Cl (120 mg, 2.25 mmol) . The resulting mixture was heated at 90℃ for 2 h while color changed from orange to brown. The reaction mixture was filtered, and the filtrate was concentrated in vacuum to give the crude residue, which was dissolved with CH 2Cl 2(20 mL) , washed with water (15 mL×3) , then dried over Na 2SO 4and concentrated in vacuum to give compound 52b (125 mg, 63%yield) as a brown solid.
[1294]
LCMS: R t=0.629 min in 5-95AB_220&254. lcm chromatography (MERCK RP18 2.5-2mm) , MS (ESI) m/z=530.1 [M+H] +.
[1295]
1H NMR (400MHz, CDCl 3) δ 8.85 (s, 1H) , 8.15 (d, J=7.2 Hz, 1H) , 8.03 (d, J=6.0 Hz, 1H) , 7.87 (s, 1H) , 7.43 (s, 1H) , 7.08 (d, J=10.4 Hz, 1H) , 6.66 (s, 1H) , 6.05 (d, J=5.6 Hz, 1H) , 3.81 (s, 3H) , 3.20 -3.11 (m, 2H) , 3.06 -2.97 (m, 2H) , 2.91 -2.83 (m, 1H) , 2.28 (s, 6H) , 2.17 -2.09 (m, 1H) , 1.92 -1.81 (m, 1H) , 1.65 (s, 6H) .
[1296]
Procedure for the preparation of Example 52:
[1297]
To a solution of compound 52b (125 mg, 0.236 mmol) and DIEA (46 mg, 0.354 mmol) in DMF (1.5 mL) was added acryloyl chloride (21 mg, 0.236 mmol) in ice water bath. The resulting mixture was stirred at 5-10℃ for 15 min. The reaction was quenched by H 2O (0.1 mL) and then filtered, the filtrate was purified by pre-HPLC directly (Column: Xtimate C18 150*25mm*5um; Condition: 35-65%B (A: 0.04%NH 3·H 2O+10mM NH 4HCO 3, B: CH 3CN) ; Flow Rate: 30 ml/min) and then lyophilized to give Example 52 (14.5 mg, 10.5%yield) as an off-white solid.
[1298]
LCMS: R t=2.028 min in 10-80CD_3min_220&254. lcm chromatography (XBrige Shield RP18 2.1*50mm, 5um) , MS (ESI) m/z=584.3 [M+H] +.
[1299]
1H NMR (400MHz, CDCl 3) δ 9.62 (s, 1H) , 9.43 (br s, 1H) , 8.59 (br s, 1H) , 8.08 (d, J=5.2 Hz, 1H) , 7.53 (d, J=6.8 Hz, 1H) , 7.47 (br s, 1H) , 7.14 (d, J=10.8 Hz, 1H) , 6.75 (s, 1H) , 6.41 -6.31 (m, 3H) , 5.77 (t, J=5.4 Hz, 1H) , 3.86 (s, 3H) , 3.15 -3.02 (m, 4H) , 2.97 -2.84 (m, 1H) , 2.30 (s, 6H) , 2.21 -2.14 (m, 1H) , 1.99 -1.94 (m, 1H) , 1.72 (s, 6H) .
PATENT
PAPER
https://www.mdpi.com/1420-3049/29/7/1448
Sunvozertinib, a novel TKI manufactured by Dizal Pharmaceuticals, represents an advancement arising from the need to overcome resistance mechanisms and thereby replaces previous generations of EGFR inhibitors. As marketed under the proprietary name DZD9008, this therapeutic entity embodies an innovative modality aimed at addressing NSCLC characterized by distinct mutations within the EGFR gene [24]. The pharmacological efficacy of sunvozertinib is predicated upon its specific capacity to inhibit EGFR with Exon 20 mutations, alongside targeting human epidermal growth factor receptor 2 (HER2) with Exon 20 insertions. This targeted inhibition is of significance due to the diminished responsiveness of cancer cells with these mutations to earlier generations of EGFR inhibitors. By competitively obstructing the ATP-binding site of these mutated tyrosine kinases, sunvozertinib effectively hinders the proliferative signaling pathways, exhibiting potent anti-tumor activity (ClinicalTrials.gov Identifier: NCT03974022). Preclinical models have demonstrated sunvozertinib’s capacity to inhibit tumor growth, especially in NSCLC models harboring Exon 20 insertions. Moreover, its substantiated ability to traverse the blood–brain barrier has provided favorable support for its prospective efficacy in managing central nervous system metastases. In clinical settings, sunvozertinib has shown promising efficacy, with ongoing trials further assessing its utility as a targeted intervention for individuals presenting specific EGFR mutations. The toxicity profile has been comparable to other EGFR inhibitors, with manageable side effects that do not significantly diminish its therapeutic value [25].
The preparation of sunvozertinib is shown in Scheme 1 [26]. SUNV-001 and SUNV-002 engage in nucleophilic substitution reactions under alkaline conditions, yielding the formation of SUNV-003 through a subsequent nucleophilic substitution process involving SUNV-004, ultimately leading to the generation of SUNV-005. SUNV-005 and SUNV-006 consecutively engage in nucleophilic substitution reactions, culminating in the formation of SUNV-007. The nitro moiety present in SUNV-007 undergoes a reduction process to yield an amino functional group, through the utilization of hydrogen gas as the reducing agent and platinum carbon as the catalytic mediator, ultimately affording the formation of SUNV-008. The amino moiety present in SUNV-008 and the acyl chloride functionality of SUNV-009 engage in a condensation reaction, leading to the formation of the amide compound SUNV-010. SUNV-010 is subjected to an elimination reaction in alkaline environments, leading to the formation of sunvozertinib.
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References
- ^ Jump up to:a b c d e f g h “FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations”. U.S. Food and Drug Administration (FDA). 2 July 2025. Retrieved 7 July 2025.
This article incorporates text from this source, which is in the public domain. - ^ Jump up to:a b Wang M, Yang JC, Mitchell PL, Fang J, Camidge DR, Nian W, et al. (2022). “Sunvozertinib, a Selective EGFR Inhibitor for Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations”. Cancer Discovery. 12 (7): 1676–1689. doi:10.1158/2159-8290.CD-21-1615. PMC 9262839. PMID 35404393.
- ^ Wang M, Fan Y, Sun M, Wang Y, Zhao Y, Jin B, et al. (2024). “Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): Single-arm, open-label, multicentre, phase 2 trial”. The Lancet Respiratory Medicine. 12 (3): 217–224. doi:10.1016/S2213-2600(23)00379-X. PMID 38101437.
- ^ Hidetoshi Hayashi (2024). “Sunvozertinib: the next candidate of TKI for NSCLC”. The Lancet Respiratory Medicine. 12 (3): 185–186. doi:10.1016/S2213-2600(23)00419-8. PMID 38101435.
- ^ “ASH: With high tumor response, AstraZeneca spinout Dizal explores FDA path and US partner for PTCL drug”. Fierce Biotech. 11 December 2023.
- ^ Dhillon S (2023). “Sunvozertinib: First Approval”. Drugs. 83 (17): 1629–1634. doi:10.1007/s40265-023-01959-5. PMID 37962831.
- ^ “FDA Grants Breakthrough Therapy Designation to Sunvozertinib in EGFR Exon20+ NSCLC”. targetedonc.com. 9 April 2024.
External links
- Clinical trial number NCT03974022 for “Assessing an Oral EGFR Inhibitor, Sunvozertinib in Patients Who Have Advanced Non-small Cell Lung Cancer with EGFR or HER2 Mutation (WU-KONG1)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | 舒沃哲, Zegfrovy |
| Routes of administration | Oral |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1]Rx in China |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2370013-12-8 |
| PubChem CID | 139377809 |
| DrugBank | DB18925 |
| UNII | L1Q2K5JYO8 |
| Chemical and physical data | |
| Formula | C29H35ClFN7O3 |
| Molar mass | 584.09 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
//////////Sunvozertinib, DZD9008, DZD 9008, FDA 2025, APPROVALS 2025, A-1801, A 1801, L1Q2K5JYO8
PALTUSOTINE
PALTUSOTINE
CAS 2172870-89-0
- CRN00808
- F2IBD1GMD3
WeightAverage: 456.497
Monoisotopic: 456.17616767
Chemical FormulaC27H22F2N4O
3-[4-(4-Amino-1-piperidinyl)-3-(3,5-difluorophenyl)-6-quinolinyl]-2-hydroxybenzonitrile
fda 2025, approvals 2025, To treat acromegaly in adults who had an inadequate response to surgery and/or for whom surgery is not an option
- OriginatorCrinetics Pharmaceuticals
- ClassAmines; Antineoplastics; Antisecretories; Fluorobenzenes; Nitriles; Piperidines; Quinolines; Small molecules
- Mechanism of ActionSomatostatin receptor 2 agonists
- Orphan Drug Status – Acromegaly
- PreregistrationAcromegaly
- Phase IIMalignant carcinoid syndrome
- 08 May 2025Crinetics Pharmaceuticals expects potential EMA decision for paltusotine in Acromegaly, in the first half of 2026
- 08 May 2025FDA assigns PDUFA action date of 25/09/2025 for paltusotine for acromegaly
- 08 May 2025Crinetics Pharamceuticals plans the phase III CAREFNDR trial for Malignant carcinoid syndrome (PO), in the second quarter of 2025
Paltusotine is a selective somatostatin receptor type 2 (SST2) agonist in development by Crinetics Pharmaceuticals for the treatment of acromegaly and certain neuroendocrine tumors. It is a small molecule delivered orally.[1][2][3][4]
SCHEME
PAPER
https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00431
Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist
Step 2-1, preparation of [1-(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tertbutyl ester: To a DMSO solution of 6-bromo-3,4-dichloroquinoline (950 mg, 1 Eq, 3.43 mmol)
was added tert-butyl piperidin-4-ylcarbamate (841 mg, 98% Wt, 1.2 Eq, 4.12 mmol) and DIPEA
(1.19 g, 1.60 mL, 3 Eq, 10.3 mmol). The resulting mixture was heated at 60 °C for overnight.
The reaction crude was quenched with water, extracted with EtOAc, washed with brine,
concentrated and purified by silica gel chromatography to afford tert-butyl (1-(6-bromo-3-
chloroquinolin-4-yl)piperidin-4-yl)carbamate (0.95 g, 2.2 mmol, 63 %) as an off-white solid. 1H
NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.25 (d, J=5 Hz, 1H), 7.94 (d, J=10 Hz, 1H), 7.74 (d,
J=10 Hz, 1H), 4.61 (s, 1H), 3.76 (s, 1H), 3.51 (m, 2H), 3.37 (m, 2H), 2.13-2.15 (m, 2H), 1.73-
1.65 (m, 2H), 1.48 (s, 9H). MS [M+H]
+= 442.0.
Step 4-2, preparation of 1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-
quinolin-4-yl}-piperidin-4-yl)-carbamic acid tert-butyl ester: To a THF (5.0 mL) solution of [1-
(6-bromo-3-chloro-quinolin-4-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (1.0 mmol, 440
mg) and 2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
benzonitrile (1.4 eq., 1.4 mmol, 460 mg) was added PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and
KOAc (3.0 eq., 3.0 mmol, 300 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 80 °C for 1 h. LCMS analysis
showed about 50% of the starting material has been converted to the desired product. Additional
2-(2-methoxy-ethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile
(1.4 eq., 1.4 mmol, 460 mg), PdCl2dppf (0.1 eq., 0.1 mmol, 75 mg) and KOAc (3.0 eq., 3.0
mmol, 300 mg) were added and the resulting solution was heated at 80 °C for another 2 h. The
reaction solution was combined with silica gel and concentrated. The residue obtained was
purified by silica gel chromatography eluting with ethyl acetate/hexane (0~50%) to give 0.512 g
of the desired product as white solid. MS [M+H]
+= 567.6.
Step 4-3, preparation of {1-[6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-3-(3,5-difluorophenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester: To a dioxane (5 mL)
solution of (1-{3-chloro-6-[3-cyano-2-(2-methoxy-ethoxymethoxy)-phenyl]-quinolin-4-yl}-
piperidin-4-yl)-carbamic acid tert-butyl ester (0.5 mmol, 283 mg) was added Pd(amphos)Cl2 (0.1
eq., 0.05 mmol, 37 mg), 3, 5-difluorophenyl boronic acid (3.0 eq., 1.5 mmol, 250 mg) and
K2CO3 (4.0 eq., 2.0 mmol, 276 mg). N2 was bubbled through the reaction solution for 5 min and
0.5 mL water was added. The resulting mixture was heated at 95 °C for 0.5 h and LCMS analysis
showed that starting material was completely consumed. The reaction solution was concentrated
with silica gel and purified by silica gel chromatography eluting with ethyl acetate/hexane
(0~50%) to give 0.170 g of the desired product as white solid. MS (M+H)+= 645.6.
Step 4-4, preparation of 3-[4-(4-amino-piperidin-1-yl)-3-(3,5-difluoro-phenyl)-quinolin-6-yl]-2-hydroxybenzonitrile: to the dichloromethane (5.0 mL) solution of {1-[6-[3-cyano-2-(2-methoxyethoxymethoxy)-phenyl]-3-(3,5-difluoro-phenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid
tert-butyl ester (0.264 mmol, 170 mg) was added trifluroroacetic acid (2.0 mL) and the resulting
mixture was stirred at ambient temperature for 2 h. The reaction solution was concentrated and
purified by C18 reversed phase chromatography eluting with MeCN/water (0~40%). Pure
fractions were combined, neutralized with saturated NaHCO3, extracted with ethyl acetate and
dried with MgSO4. The organic solution was concentrated with HCl in ether (2.0 M) to give the
final compound as HCl salt (68 mg, 0.138 mmol, 52%).
1H NMR (500 MHz, DMSO-d6) δ 10.77
(br s, 1H), 8.78 (s, 1H), 8.29-8.15 (m, 5H), 7.79 (dd, J=20 Hz, 5 Hz, 2H), 7.41 (m, 1H), 7.26-
7.19 (m, 3H), 3.59 (t, J=12 Hz, 2H), 3.31 (m, 1H), 3.00 (t, J=12 Hz, 2H), 2.05-1.99 (m, 2H),
1.76-1.74 (m, 2H). MS [M+H]
+= 457.5. 13C NMR (DMSO-d6) δ 30.2, 47.4, 50.8, 102.4, 103.2,
113.4, 117.2, 121.4, 124.6, 130.7, 133.1, 134.6, 136.0, 141.7, 156.6, 161.2, 163.2. LCMS purity
98% (254&220 nM). HRMS m/z [M+H]+ Calcd for C27H23F2N4O 457.1834; found 457.1833.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US235548187&_cid=P20-MCSHXW-73235-1
PATENTS
WO2021011641
WO2018013676
References
- ^ Madan, Ajay; Markison, Stacy; Betz, Stephen F.; Krasner, Alan; Luo, Rosa; Jochelson, Theresa; Lickliter, Jason; Struthers, R. Scott (April 2022). “Paltusotine, a novel oral once-daily nonpeptide SST2 receptor agonist, suppresses GH and IGF-1 in healthy volunteers”. Pituitary. 25 (2): 328–339. doi:10.1007/s11102-021-01201-z. PMC 8894159. PMID 35000098.
- ^ Zhao, Jian; Wang, Shimiao; Markison, Stacy; Kim, Sun Hee; Han, Sangdon; Chen, Mi; Kusnetzow, Ana Karin; Rico-Bautista, Elizabeth; Johns, Michael; Luo, Rosa; Struthers, R. Scott; Madan, Ajay; Zhu, Yunfei; Betz, Stephen F. (12 January 2023). “Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist”. ACS Medicinal Chemistry Letters. 14 (1): 66–74. doi:10.1021/acsmedchemlett.2c00431. PMC 9841592. PMID 36655128.
- ^ Gadelha, Monica R; Gordon, Murray B; Doknic, Mirjana; Mezősi, Emese; Tóth, Miklós; Randeva, Harpal; Marmon, Tonya; Jochelson, Theresa; Luo, Rosa; Monahan, Michael; Madan, Ajay; Ferrara-Cook, Christine; Struthers, R Scott; Krasner, Alan (13 April 2023). “ACROBAT Edge: Safety and Efficacy of Switching Injected SRLs to Oral Paltusotine in Patients With Acromegaly”. The Journal of Clinical Endocrinology & Metabolism. 108 (5): e148 – e159. doi:10.1210/clinem/dgac643. PMC 10099171. PMID 36353760. S2CID 253445337.
- ^ Zhao, Jie; Fu, Hong; Yu, Jingjing; Hong, Weiqi; Tian, Xiaowen; Qi, Jieyu; Sun, Suyue; Zhao, Chang; Wu, Chao; Xu, Zheng; Cheng, Lin; Chai, Renjie; Yan, Wei; Wei, Xiawei; Shao, Zhenhua (21 February 2023). “Prospect of acromegaly therapy: molecular mechanism of clinical drugs octreotide and paltusotine”. Nature Communications. 14 (1): 962. Bibcode:2023NatCo..14..962Z. doi:10.1038/s41467-023-36673-z. ISSN 2041-1723. PMC 9944328. PMID 36810324.
| Legal status | |
|---|---|
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2172870-89-0 |
| PubChem CID | 134168328 |
| ChemSpider | 81367268 |
| UNII | F2IBD1GMD3 |
| Chemical and physical data | |
| Formula | C27H22F2N4O |
| Molar mass | 456.497 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
////////PALTUSOTINE, ORPHAN DRUG, Acromegaly, CRN 00808, F2IBD1GMD3, fda 2025, approvals 2025
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Taletrectinib
Taletrectinib
CAS 1505514-27-1
as salt: 1505515-69-4, Taletrectinib adipate
FDA 6/11/2025, Ibtrozi, To treat locally advanced or metastatic ROS1-positive non-small cell lung cancer ALSO CHINA 2024 APPROVED |
405.5 g/mol, C23H24FN5O, UNII-W4141180YD
3-[4-[(2R)-2-aminopropoxy]phenyl]-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine
Taletrectinib adipate
WeightAverage: 551.619
Monoisotopic: 551.254397378
Chemical FormulaC29H34FN5O5
DS-6051B, CAS 1505515-69-4,
6KLL51GNBG, 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine; hexanedioic acid
Taletrectinib, sold under the brand name Ibtrozi, is an anti-cancer medication used for the treatment of non-small cell lung cancer.[1][2] It is used as the salt, taletrectinib adipate.[1] Taletrectinib is a kinase inhibitor.[1] It is taken by mouth.[1]
Taletrectinib was approved for medical use in the United States in June 2025.[3]
SYN
US20200062765
https://patentscope.wipo.int/search/en/detail.jsf?docId=US289038418&_cid=P12-MCIHV1-02369-1
Example 1
tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)
Example 2
6-Fluoroimidazo[1,2-b]pyridazine methanesulfonate (2)
Example 3
tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)
Example 4
tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)
Example 5
3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023272701&_cid=P12-MCIHPU-95869-1
The NMR data for the crystalline form A of Compound 1 adipate are as follows: 1H NMR (500 MHz, DMSO) δ 1.13-1.14 (d, J=5.0 Hz, 3H) , 1.47-1.48 (d, J=5.0 Hz, 7H) , 2.15-2.18 (t, J=5.0 Hz, J=10.0 Hz, 4H) , 3.25-3.29 (m, 1H) , 3.79-3.83 (m, 2H) , 4.80-4.85 (m, 1H) , 6.76-6.77 (d, J=5.0 Hz, 1H) , 6.92-6.94 (d, J=10.0 Hz, 2H) , 7.01-7.05 (t, J=10.0 Hz, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.64-7.65 (d, J=5.0 Hz, 1H) , 7.72-7.76 (t, J=10.0 Hz, 4H) .
[0148]
The IR data for the crystalline form A of Compound 1 adipate are as follows: IR (cm -1) : 1701, 1628, 1612, 1586, 1463, 1333, 1246, 1110, 829, 821.
Example 5: Preparation and Characterization of Crystalline Form A of Compound 1 Free Base
[0212]
Compound 1 HCl (75.5 g) (e.g., obtained by using the method described in Example 5 of U.S. Application Publication No. 2020/0062765) was dissolved in ethanol (604 mL) at 50℃. Sodium hydroxide (68.1 g) was added to the above solution. The mixture was cooled to 1℃ in 1.5 hours and stirred for 18.5 hours. The mixture was then filtered, and the solid thus obtained was washed with a cooled mixture of ethanol (151 mL) and water (151 mL) and dried. The solid thus obtained was confirmed to be the crystalline form A of Compound 1 free base.
[0213]
The NMR data for the crystalline form A of Compound 1 free base are as follows: 1H NMR (500 MHz, DMSO) δ 1.09-1.10 (d, J=5.0 Hz, 3H) , 1.48-1.49 (d, J=5.0 Hz, 3H) , 3.16-3.20 (m, 1H) , 3.75-3.79 (m, 2H) , 4.82-4.86 (m, 1H) , 6.76-6.78 (d, J=10.0 Hz, 1H) , 6.92-6.94 (m, 2H) , 7.01-7.05 (m, 1H) , 7.23-7.28 (m, 2H) , 7.37-7.42 (m, 1H) , 7.62-7.63 (d, J=5.0 Hz, 1H) , 7.72-7.75 (m, 4H) .
[0214]
The IR data for the crystalline form A of Compound 1 free base are as follows: IR (cm -1) : 3350, 3247, 3055, 2961, 2923, 2864, 1611, 1586, 1349, 829, 819.
SYN
European Journal of Medicinal Chemistry 291 (2025) 117643
Taletrectinib is an oral, next-generation ROS1 TKI developed by Nuvation Bio Inc. for the treatment of ROS1-positive NSCLC. In 2024, the NMPA approved taletrectinib for adult patients with locally advanced or metastatic ROS1-positive NSCLC, regardless of prior ROS1TKI treatment [47]. Under an exclusive license agreement, Innovent Biologics will commercialize taletrectinib in China under the brand
name DOVBLERON®. Taletrectinib exerts its pharmacological action through the mechanism of selectively impeding the ROS1 receptor tyrosine kinase, which effectively disrupts the signaling cascades which are responsible for facilitating the growth and survival of cancer cells in ROS1-positive NSCLC. This inhibition of the ROS1 receptor tyrosine kinase is a key event in the drug’s mode of action, as it specifically targets the molecular processes that drive the progression of the disease in ROS1-positive NSCLC cases [48]. The NMPA granted approval founded on the data sourced from the crucial Phase 2 TRUST – I study. This study substantiated that patients administered with taletrectinib achieved sustained responses and extended PFS. Regarding safety, taletrectinib boasted a generally good tolerability. It presented an advantageous safety profile and favorable tolerability characteristics, as evidenced by the low incidences of dose reduction and treatment discontinuation triggered by adverse effects. [49]. Overall, taletrectinib represents a promising therapeutic option for patients with advanced ROS1-positive NSCLC, offering efficacy in both TKI-naïve and TKI-pretreated populations, including those with CNS metastases [50–52].
The synthesis of Taletrectinib, illustrated in Scheme 12, commences with Mitsunobu coupling of Tale-001 and Tale-002 to afford Tale-003, which then undergoes Suzuki coupling with Tale-004 constructing
Tale-005 [53]. Sequential acidolysis/deprotection of Tale-005 ultimately delivers Taletrectinib
[47] M. P´ erol, N. Yang, C.M. Choi, Y. Ohe, S. Sugawara, N. Yanagitani, G. Liu, F.G.M.
D. Braud, J. Nieva, M. Nagasaka, 1373P efficacy and safety of taletrectinib in
patients (pts) with ROS1+ non-small cell lung cancer (NSCLC): interim analysis of
global TRUST-II study, Ann. Oncol. 34 (2023) S788–S789.
[48] G. Harada, F.C. Santini, C. Wilhelm, A. Drilon, NTRK fusions in lung cancer: from
biology to therapy, Lung Cancer 161 (2021) 108–113.
[49] W. Li, A. Xiong, N. Yang, H. Fan, Q. Yu, Y. Zhao, Y. Wang, X. Meng, J. Wu, Z. Wang,
Y. Liu, X. Wang, X. Qin, K. Lu, W. Zhuang, Y. Ren, X. Zhang, B. Yan, C.M. Lovly,
C. Zhou, Efficacy and safety of taletrectinib in Chinese patients with ROS1+ non-
small cell lung cancer: the phase II TRUST-I study, J. Clin. Oncol. 42 (2024)
2660–2670.
[50] M. Nagasaka, D. Brazel, S.I. Ou, Taletrectinib for the treatment of ROS-1 positive
non-small cell lung cancer: a drug evaluation of phase I and II data, Expert Opin
Investig Drugs 33 (2024) 79–84.
[51] S. Waliany, J.J. Lin, Taletrectinib: TRUST in the continued evolution of treatments
for ROS1 fusion-positive lung cancer, J. Clin. Oncol. 42 (2024) 2622–2627.
[52] M. Nagasaka, Y. Ohe, C. Zhou, C.M. Choi, N. Yang, G. Liu, E. Felip, M. P´ erol,
B. Besse, J. Nieva, L. Raez, N.A. Pennell, A. Dimou, F. Marinis, F. Ciardiello,
T. Seto, Z. Hu, M. Pan, W. Wang, S. Li, S.I. Ou, TRUST-II: a global phase II study of
taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors,
Future Oncol. 19 (2023) 123–135.
[53] Y. Takeda, K. Yoshikawa, Y. Kagoshima, Y. Yamamoto, R. Tanaka, Y. Tominaga,
M. Kiga, Y. Hamada, Preparation of imidazo[1,2-b]pyridazine Derivatives as
Potent Inhibitors of ROS1 Kinase and NTRK Kinase, 2013. WO2013183578A1.
Medical uses
Taletrectinib is indicated for the treatment of adults with locally advanced or metastatic ROS1-positive non-small cell lung cancer.[1][2]
Adverse effects
The FDA prescribing information for taletrectinib includes warnings and precautions for hepatotoxicity, interstitial lung disease/pneumonitis, QTc interval prolongation, hyperuricemia, myalgia with creatine phosphokinase elevation, skeletal fractures, and embryo-fetal toxicity.[1][3]
History
The efficacy of taletrectinib to treat ROS1-positive non-small cell lung cancer was evaluated in participants with locally advanced or metastatic, ROS1-positive non-small cell lung cancer enrolled in two multi-center, single-arm, open-label clinical trials, TRUST-I (NCT04395677) and TRUST-II (NCT04919811).[3] The efficacy population included 157 participants (103 in TRUST-I; 54 in TRUST-II) who were naïve to treatment with a ROS1 tyrosine kinase inhibitor (TKI) and 113 participants (66 in TRUST-I; 47 in TRUST-II) who had received one prior ROS1 tyrosine kinase inhibitor.[3] Participants may have received prior chemotherapy for advanced disease.[3] The US Food and Drug Administration (FDA) granted the application for taletrectinib priority review, breakthrough therapy, and orphan drug designations.[3]
Society and culture
Legal status
Taletrectinib was approved for medical use in the United States in June 2025.[3][4]
Names
Taletrectinib is the international nonproprietary name.[5]
Taletrectinib is sold under the brand name Ibtrozi.[3][4]
References
- ^ Jump up to:a b c d e f g “Prescribing Information for NDA 219713, Supplement 000” (PDF). Drugs@FDA. U.S. Food and Drug Administration. April 2025. Retrieved 14 June 2025.
- ^ Jump up to:a b Khan I, Sahar A, Numra S, Saha N, Nidhi, Parveen R (April 2025). “Efficacy and safety of taletrectinib for treatment of ROS1 positive non-small cell lung cancer: A systematic review”. Expert Opinion on Pharmacotherapy. 26 (6): 765–772. doi:10.1080/14656566.2025.2487150. PMID 40170301.
- ^ Jump up to:a b c d e f g h “FDA approves taletrectinib for ROS1-positive non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 11 June 2025. Retrieved 13 June 2025. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “U.S. Food and Drug Administration Approves Nuvation Bio’s Ibtrozi (taletrectinib), a Next-Generation Oral Treatment for Advanced ROS1-Positive Non-Small Cell Lung Cancer”. Nuvation Bio (Press release). 12 June 2025. Retrieved 13 June 2025.
- ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 85”. WHO Drug Information. 35 (1). hdl:10665/340684.
External links
- Clinical trial number NCT04395677 for “A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene” at ClinicalTrials.gov
- Clinical trial number NCT04919811 for “Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC (TRUST-II)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Ibtrozi |
| License data | US DailyMed: Taletrectinib |
| Routes of administration | By mouth |
| Drug class | Antineoplastic |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 1505514-27-1as salt: 1505515-69-4 |
| PubChem CID | 72202474as salt: 72694302 |
| DrugBank | DB18711 |
| ChemSpider | 114934673as salt: 88297530 |
| UNII | W4141180YDas salt: 6KLL51GNBG |
| KEGG | D12363as salt: D12364 |
| ChEMBL | ChEMBL4650989as salt: ChEMBL4650361 |
| Chemical and physical data | |
| Formula | C23H24FN5O |
| Molar mass | 405.477 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
/////////Taletrectinib, FDA 2025, APPROVALS 2025, Ibtrozi, CANCER, AB-106, DS-6051a, UNII-W4141180YD, DS 6051B, APPROVALS 2024, CHINA 2024, Nuvation Bio Inc
Acoltremon
Acoltremon
CAS 68489-09-8
WeightAverage: 289.419
Monoisotopic: 289.204179113
Chemical FormulaC18H27NO2
FDA 2025, 5/28/2025, To treat the signs and symptoms of dry eye disease
Tryptyr |
WS 12
(1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(propan-2-yl)cyclohexane-1-carboxamide
Fema No. 4681
N-(4-methoxyphenyl)-p-menthanecarboxamide
- OriginatorInstituto de Neurociencias de Alicante
- DeveloperAlcon; AVX Pharma
- ClassCyclohexanes; Ethers; Eye disorder therapies; Small molecules
- Mechanism of ActionTRPM8 protein stimulants
- RegisteredDry eyes
- 30 May 2025Alcon plans to launch Acoltremon for Dry eyes in USA in the third quarter of 2025
- 28 May 2025Registered for Dry eyes in USA (Ophthalmic) – First global approval
- 05 May 2025FDA assigns PDUFA action date of 30/05/2025 for Acoltremon for Dry eyes
Acoltremon sold under the brand name Tryptyr, is a medication used for the treatment of dry eye syndrome.[1]
PATENT
US 217370
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023114986&_fid=RU437402572
https://patentscope.wipo.int/search/en/detail.jsf?docId=US193167995&_cid=P11-MCE7BB-27500-1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012032209&_fid=US193167995
Medical uses
Acoltremon was approved for medical use in the United States in May 2025, for the treatment of signs and symptoms associated with dry eye disease.[2]
Pharmacology
Acoltremon acts as a potent and selective activator (opener) of the TRPM8 calcium channel, which is responsible for the sensation of coldness produced by menthol.[3] It is slightly less potent as a TRPM8 activator compared to icilin, but is a much more selective TRPM8 ligand when compared to menthol.[4]
Society and culture
Legal status
Acoltremon was approved for medical use in the United States in May 2025.[5]
References
- ^ Jump up to:a b https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/217370s000lbl.pdf
- ^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 29 May 2025. Archived from the original on 3 March 2025. Retrieved 29 May 2025.
- ^ Ma S, Gisselmann G, Vogt-Eisele AK, Doerner JF, Hatt H (October 2008). “Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels”. Pakistan Journal of Pharmaceutical Sciences. 21 (4): 370–378. PMID 18930858.
- ^ Kühn FJ, Kühn C, Lückhoff A (February 2009). “Inhibition of TRPM8 by icilin distinct from desensitization induced by menthol and menthol derivatives”. The Journal of Biological Chemistry. 284 (7): 4102–4111. doi:10.1074/jbc.M806651200. PMID 19095656.
- ^ “Alcon Announces FDA Approval of Tryptyr (acoltremon ophthalmic solution) 0.003% for the Treatment of the Signs and Symptoms of Dry Eye Disease” (Press release). Alcon. 28 May 2025. Archived from the original on 29 May 2025. Retrieved 29 May 2025 – via Business Wire.
External links
- Clinical trial number NCT05285644 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-2)” at ClinicalTrials.gov
- Clinical trial number NCT05360966 for “Study Evaluating the Safety and Efficacy of AR-15512 (COMET-3)” at ClinicalTrials.gov
| molecular structure | |
| 3D representation | |
| Clinical data | |
|---|---|
| Trade names | Tryptyr |
| Other names | AVX-012, WS-12 |
| License data | US DailyMed: Acoltremon |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 68489-09-8 |
| PubChem CID | 11266244 |
| DrugBank | DB19202 |
| ChemSpider | 9441255 |
| UNII | 1L7BVT4Z4Z |
| KEGG | D13125 |
| ChEMBL | ChEMBL2441929 |
| CompTox Dashboard (EPA) | DTXSID10460636 |
| Chemical and physical data | |
| Formula | C18H27NO2 |
| Molar mass | 289.419 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Beck B, et al. Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators. Cell Calcium. 2007 Mar;41(3):285-94. [Content Brief][2]. Ma S, et al. Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels. Pak J Pharm Sci. 2008 Oct;21(4):370-8. [Content Brief]
///////Acoltremon, FDA 2025, APPROVALS 2025, WS-12, WS 12, Fema No. 4681, Tryptyr, 1L7BVT4Z4Z, AR-15512
Nerandomilast
Nerandomilast
CAS 1423719-30-5
C20H25ClN6O2S
| Molecular Weight | 448.97 |
|---|---|
| Formula | C20H25ClN6O2S |
fda 2025, approvals 2025, Jascayd,10/7/2025, To treat idiopathic pulmonary fibrosis
[1-[[(5R)-2-[4-(5-chloropyrimidin-2-yl)piperidin-1-yl]-5-oxo-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutyl]methanol
Cyclobutanemethanol, 1-[[(5R)-2-[4-(5-chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]-
1-[[(5R)-2-[4-(5-Chloro-2-pyrimidinyl)-1-piperidinyl]-6,7-dihydro-5-oxidothieno[3,2-d]pyrimidin-4-yl]amino]cyclobutanemethanol
Nerandomilast (BI 1015550) is an investigational oral medication being studied for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). It is a preferential inhibitor of phosphodiesterase 4B (PDE4B) and has shown potential in slowing lung function decline in patients with IPF.
Key points about nerandomilast:
- Mechanism of Action:Nerandomilast inhibits PDE4B, an enzyme that plays a role in inflammation and fibrosis.
- Clinical Trials:Phase 3 clinical trials have shown that nerandomilast can slow lung function decline in patients with IPF and PPF.
- Efficacy:The trials demonstrated that nerandomilast led to a smaller decline in forced vital capacity (FVC), a measure of lung function, compared to placebo.
- Safety:Diarrhea was the most frequent adverse event, but serious adverse events were balanced across treatment groups.
- Progressive Fibrosing ILDs:Nerandomilast is also being investigated in other progressive fibrosing interstitial lung diseases (ILDs) beyond IPF.
- FDA Designation:Nerandomilast received Breakthrough Therapy Designation from the FDA for the treatment of IPF.
- Not a Cure:While nerandomilast can slow disease progression, it does not cure pulmonary fibrosis.
- Not Yet Approved:Nerandomilast is still an investigational drug and is not yet approved for use.
Nerandomilast (BI 1015550) is an orally active inhibitor of PDE4B with an IC50 value of 7.2 nM. Nerandomilast has good safety and potential applications in inflammation, allergic diseases, pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).
SCHEME
1H NMR (400 MHz, DMSO-D6) 1.57–1.84 (m, 2H), 1.96 (br d, J = 12.5 Hz, 2H), 2.10–2.21 (m, 2H), 2.24–
2.41 (m, 2H), 2.82–2.98 (m, 2H), 3.06 (br t, J = 11.7 Hz, 2H), 3.13–3.27 (m, 2H), 3.36–3.47 (m, 1H), 3.71 (d, J =
5.64 Hz, 2H), 4.70 (br d, J = 12.5 Hz, 2H), 4.84 (t, J = 5.7 Hz, 1H), 7.35 (s, 1H), 8.85 (s, 2H).
1H NMR (DMSO-d6, 400 MHz) 1.87–1.92 (m, 2H), 2.12–2.17 (m, 2H), 3.08 (ddd, J = 12.8, 12.8, 2.8 Hz,
2H), 3.21 (m, 1H), 3.34–3.42 (m, 2H), 8.47 (br, 2H), 8.19 (s, 2H).
PATENT
US20150045376
WO2013026797
PAPER
https://pubs.acs.org/doi/10.1021/acs.oprd.4c00309
A robust and scalable synthesis process for Nerandomilast (1, BI 1015550), a selective PDE4B inhibitor with potential therapeutic properties for the treatment of respiratory diseases, was developed and implemented at a pilot plant on a multikilogram scale. Key aspects of the process include the efficient synthesis of intermediate (1-((2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)cyclobutyl)methanol (4) by means of a regioselective SNAr reaction between (1-aminocyclobutyl)methanol (6) and 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5), a new convergent synthesis of 5-chloro-2-(piperidin-4-yl)pyrimidine (3) by means of a Suzuki coupling, and a highly enantioselective sulfide oxidation to give chiral nonracemic (R)-2-chloro-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (2).
- [1]. Pouzet P A, et al. Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma. United States. US9150586.[2]. Herrmann FE, et al. BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022 Apr 20;13:838449. [Content Brief]
//////////Nerandomilast, BI 1015550, I5DGT51IB8, fda 2025, approvals 2025, Jascayd,
Acoramidis
Acoramidis
- AG-10
- 1446711-81-4
- AG10
- Acorami
292.30 g/mol,
C15H17FN2O3
3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid
FDA APPROVED 11/22/2024, Attruby To treat cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis
Drug Trials Snapshot
| Ingredient | UNII | CAS | InChI Key |
|---|---|---|---|
| Acoramidis hydrochloride | VY9C88C2NV | 2242751-53-5 | MGFZEARHINUOMX-UHFFFAOYSA-N |
Acoramidis, sold under the brand name Attruby, is a medication used for the treatment of cardiomyopathy.[1] It is a near-complete (>90%) transthyretin stabilizer, developed to mimic the protective properties of the naturally-occurring T119M mutation,[4][5] to treat transthyretin amyloid cardiomyopathy. It is taken by mouth.[1]
The most common adverse reactions include diarrhea and upper abdominal pain.[6]
Acoramidis was approved for medical use in the United States in November 2024,[6][7][8][9] and in the European Union in February 2025.[2][3]
PATENTS
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | |
|---|---|---|---|---|
| US9169214 | No | 2015-10-27 | 2031-05-05 |  |
| US9913826 | No | 2018-03-13 | 2033-03-14 | |
| US11058668 | No | 2021-07-13 | 2039-03-22 | |
| US10842777 | No | 2020-11-24 | 2031-05-05 | |
| US11919865 | No | 2024-03-05 | 2038-02-16 | |
| US12070449 | No | 2024-08-27 | 2039-03-22 | |
| US12005043 | No | 2024-06-11 | 2039-08-16 | |
| US10398681 | No | 2019-09-03 | 2031-05-05 | |
| US9642838 | No | 2017-05-09 | 2031-05-05 | |
| US8877795 | No | 2014-11-04 | 2031-05-05 | |
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | |
|---|---|---|---|---|
| US10513497 | No | 2019-12-24 | 2038-02-16 | |
| US11260047 | No | 2022-03-01 | 2039-08-16 | |
SYN
Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, Rappley I, Vogel H, Liedtke M, Witteles RM, Powers ET, Reixach N, Chan WK, Wilson IA, Kelly JW, Graef IA, Alhamadsheh MM: AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9992-7. doi: 10.1073/pnas.1300761110. Epub 2013 May 28
PATENT
https://patents.google.com/patent/US9913826B2/en
Chemical Synthesis
Methyl 3-(3-bromopropoxy)-4-fluorobenzoate (Compound 2)
To a solution of methyl 4-fluoro-3-hydroxybenzoate 1 (3.0 g, 17.6 mmol, 1 equiv) and 1,3-dibromopropane (9.0 ml, 88.2 mmol, 5 equiv) in DMF (40 ml) was added K2CO3 (2.93 g, 21.2 mmol, 1.2 equiv). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (1.5 L), washed with brine (3×0.5 L) and dried with Na2SO4. The solution was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 1-10% EtOAc/hexanes) to afford compound 2 (4.21 g, 82% yield); 1H NMR (CD3OD, 600 MHz) δ 7.67-7.61 (m, 2H), 7.14-7.07 (m, 1H), 4.21 (t, 2H, J=5.89 Hz), 3.89 (s, 3H), 3.62 (t, 2H, J=6.38 Hz), 2.38-2.31 (m, 2H); (ESI+) m/z: calcd for C11H12BrFO3+H+290.00; found 290.01 (M+H+).Methyl 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoate (Compound 4)
A solution of 2 (780 mg, 2.69 mmol, 1 equiv) in benzene (3 ml) was added dropwise to a solution of acetyl acetone (0.552 ml, 5.38 mmol, 2 equiv) and DBU (0.804 ml, 5.38 mmol, 2 equiv) in benzene (7 ml). The reaction mixture was stirred at room temperature for 3 days. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 1-10% EtOAc/hexanes) to afford compound 3 which was used in the next step directly. Hydrazine hydrate (0.36 ml, 6.73 mmol, 2.5 equiv) was added to a solution 3 in ethanol (5 ml) and the reaction was heated under reflux for 4 hours. The reaction was concentrated and purified by flash column chromatography (silica gel, 1-20% MeOH/CH2Cl2) to afford compound 4 (288 mg, 35% yield) in two steps; 1H NMR (CD3OD, 600 MHz) δ 7.64-7.58 (m, 2H), 7.20-7.15 (m, 1H), 4.01 (t, 2H, J=6.0 Hz), 3.86 (s, 3H), 2.58 (t, 2H, J=7.2 Hz), 2.12 (s, 6H), 1.97-1.92 (m, 2H); HRMS (DART) m/z: calcd for C16H19FN2O+H+307.1458; found 307.1452 (M+H+).3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid (Compound VIIc)
To a suspension of 4 (100 mg, 0.33 mmol, 1 equiv) in a mixture of THF (3 ml) and water (3 ml) was added LiOH.H2O (27.5 mg, 0.66 mmol, 2 equiv). The reaction mixture was stirred at room temperature for 14 hr after which it was cooled to 0° C. and carefully acidified to pH 2-3 with IN aqueous HCl. The mixture was extracted with EtOAc (3×30 ml) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was subjected to flash column chromatography (silica gel, 10-50% MeOH/CH2Cl2) to give Compound VIIc (68 mg, 71% yield) as a white solid (>98% purity by HPLC); 1H NMR (CD3OD, 600 MHz) δ 7.65-7.58 (m, 2H), 7.20-7.14 (m, 1H), 4.00 (t, 2H, J=6.0 Hz), 2.58 (t, 2H, J=5.8 Hz), 2.12 (s, 6H), 1.97-1.92 (m, 2H); HRMS (DART) m/z: calcd for C15H17FN2O3+H+ 293.1301; found 293.1293 (M+H+).3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzamide
To a suspension of 4 (100 mg, 0.33 mmol, 1 equiv) in a mixture of THF (3 ml) and water (3 ml) is added (23.1 mg, 0.66 mmol, 2 equiv) of NH4OH. The reaction mixture is stirred at room temperature for 14 hr after which it is cooled to 0° C. and carefully adjusted to pH 7 with IN aqueous HCl. The mixture is extracted with EtOAc (3×30 ml) and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is subjected to flash column chromatography (silica gel, 10-50% MeOH/CH2Cl2) to give 3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzamide.N-ethyl 3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzamide
To a suspension of 4 (100 mg, 0.33 mmol, 1 equiv) in a mixture of THF (3 ml) and water (3 ml) is added (27.1 mg, 0.66 mmol, 2 equiv) of C2H5NH2. The reaction mixture is adjusted to pH 9.0 with 0.5N NaOH, then stirred at room temperature for 14 hr after which it is cooled to 0° C. and carefully adjusted to pH 7 with IN aqueous HCl. The mixture is extracted with EtOAc (3×30 ml) and the combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product is subjected to flash column chromatography (silica gel, 10-50% MeOH/CH2Cl2) to give N-ethyl 3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzamide.
PATENT
https://patents.google.com/patent/US10513497B2/en
Example 1Preparation of 3-(3-Hydroxy-propyl)-pentane-2, 4-dione (a Compound of Formula IV)
A compound of Formula IIIa (100 g, 495 mmol 1.0 equiv.) was dissolved in acetone (1 L). A compound of Formula II (49.59 g, 495 mmol, 1.0 equiv.) was added to above solution, followed by addition of K2CO3 (82.14 g, 594.38 mmol, 1.2 equiv.) and KI (41.11 g, 247 mmol, 0.5 equiv.) at room temperature with stirring. The reaction mixture was heated to 60±5° C. and stirred for 40 h at this temperature. The reaction mixture was filtered and then concentrated under reduced pressure to afford a compound of Formula IV (102 g) as viscous orange liquid.Example 2Preparation of 3(3, 5-Dimethyl-1H-pyrazol-4-yl) propane-1-ol (a compound of Formula V)
A compound of Formula IV (100 g, 632 mmol, 1.0 equiv.) was dissolved in ethanol (1 L). Hydrazine hydrate (87 g, 1738 mmol, 2.75 equiv.) and conc. HCl (4.6 mL, 0.2 equiv.) were added to above solution at room temperature. The reaction mixture was heated to 75±5° C. and stirred for 3 h at this temperature. After completion of reaction by TLC (70% ethyl acetate: n-hexane, visible in iodine) and observation of product peak in mass spectrum, the reaction mixture was concentrated under reduce pressure to afford a compound of Formula V (70 g) as a colorless liquid syrup which was used as such for next step.Example 3Preparation of 4-(3-Bromo-propyl)-3, 5-dimethyl-1H-pyrazole (a compound of formula VIa)
A compound of Formula V (35 g, 227 mmol, 1.0 equiv.) was dissolved in 1,2-dichloroethane (525 mL). PBr3 (64.67mL, 681 mmol, 3 equiv.) was added in small portions at room temperature over 30 minutes. The reaction mixture was heated up to 75±5° C. and stirred for 3 h at this temperature. After completion of reaction by TLC (50% ethyl acetate: n-hexane, visible in iodine) and observation of product peak in Mass spectrum, the reaction mixture was diluted with dichloromethane (350 mL) and quenched with saturated solution of NaHCO3 till pH=7 to 8. Both organic and aqueous layers were separated and collected. The organic layer was dried over MgSO4 and filtered. Filtrate was concentrated under reduce pressure to afford a compound of Formula VIa (38 g) as a viscous orange liquid.Example 4Preparation of 3-[3-(3, 5-Dimethyl-1H-pyrazol-4-yl)-propoxy]-4-fluoro-benzoic acid methyl ester (a compound of Formula VIIIa)
A compound of Formula VIIa (19 g, 111 mmol, 1.0 equiv.) was dissolved in DMF (190 mL). A compound of Formula VIa (31.5 g, 145.14 mmol, 1.3 equiv.) was added followed by K2CO3 (38.6 g, 279.18 mmol, 2.5 equiv.) at room temperature under stirred conditions. The reaction mixture was stirred for 16 to 18 h at room temperature. After completion of reaction in TLC (50% ethyl acetate: n- hexane), the reaction mixture was diluted with water (190 mL) and ethyl acetate (95 mL). Both organic layer and aqueous layer were separated and collected. Aqueous layer was extracted with ethyl acetate (190 mL). The combined organic extract was washed with water (95 mL), brine (95 mL), dried over Na2SO4 and filtered. The filtered organic layer was concentrated under reduce pressure to afford a crude viscous orange liquid (40 g). The crude was further purified by column chromatography using silica gel (285 g) and eluted with varying quantity of ethyl acetate in hexane to afford pure product, a compound of Formula VIIIa (25 g) as an off white solid.Example 5Preparation of 3-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-propoxy]-4-fluoro-benzoic acid methyl ester (a compound of Formula VIIIa)
4-(3-Bromopropyl)-3,5-dimethyl-1H-pyrazole hydrobromide (VIa) and DMSO were charged into vessel and agitated at 20±10° C. for 10 minutes. The mixture was then heated to 55±5° C. with stirring. To this mixture was transferred a stirred solution containing 4-fluoro-3-hydroxy-benzoic acid methyl ester (VIIa), potassium carbonate and anhydrous DMSO. The DMSO solution of the alkyl bromide were slowly transferred in order to maintaining an internal temperature of 55.0±5° C. Addition was complete after 6 hours and the mixture was agitated at 55.0±5° C. for an additional hour at 55.0±5° C. The mixture was cooled to 25±5° C. over the course of 30 minutes and water added while maintaining a temperature below 25° C. The mixture was extracted with ethyl acetate and the aqueous layer back extracted with ethyl acetate. The pooled ethyl acetate solutions were washed brine. The combined ethyl acetate washes were concentrated under vacuum to a minimal volume and heptane was added, which precipitates VIIIa. The mixture was heated to 75±5° C. and aged with stirring for 1 hour. The mixture was cooled to 25±5° C. over the course of two hours and the resulting solids collected by filtration. The filter cake was washed with ethyl acetate in heptane (30%). Isolated solids were dried with a nitrogen flow. Solids are charged to vessel and combined with ethyl acetate and heptane. The resulting mixture is heated to 75±5° C. to dissolve solids. The solution was cooled to 25±5° C. over the course of two hours and the resulting solids collected by filtration. The solids were washed with a 30% ethyl acetate/heptane solvent mixture and dried in vacuum oven at 55° C. to give VIIIa in >99.5% purity.Example 6Preparation of 3-[3-(3, 5-Dimethyl-1H-pyrazol-4-yl)-propoxy]-4-fluoro-benzoic acid (a compound of Formula IX)
A compound of Formula VIIIa (19 g, 62 mmol, 1 equiv.) was dissolved in methanol (95 mL, 5 vol.) at room temperature. A solution of LiOH.H2O (6.5 g, 155 mmol, 2.5 equiv.) in water (57 mL) was added in small portions at room temperature over 10 to 15 minutes. The reaction mixture was stirred for 2 h at room temperature. After completion of reaction by TLC (70% ethyl acetate: n-hexane), the reaction mixture is concentrated below 45° C. under reduced pressure to afford a solid residue of Formula IX.Example 7Preparation of a Pharmaceutically Acceptable Salt of Formula I
The solid residue of Formula IX was dissolved in water (57 mL) and stirred for 10 min and cooled to 0±5° C. The aqueous solution was acidified with conc. HCl (20-25 mL) to pH=2 and stirred for 30 minutes at 0±5° C. Precipitation was observed which was filtered and dried at room temperature to afford pure product, a compound of Formula Ia (17.5 g) as an off-white solid.Example 8Additional Preparation of a Pharmaceutically Acceptable Salt of Formula I
Water and concentrated HCl were charged to a vessel and cooled with stirring to 10±5° C. Compound of Formula IX and water were charged to a second vessel and cooled with stirring to 10±5° C. The HCl solution in vessel
1 was transferred to a vessel containing compound of Formula IX mixture over not less than 15 minutes, while maintaining a temperature of <25° C. The resulting slurry was aged with stirring at 20±5° C. for 44 hours. The solids were collected by filtration, washed with 0.2 N HCl (3 ×) and dried under vacuum at ≥55° C. to provide Ia as white solid, >99.8% purity.Example 9Preparation of 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid hydrochloride salt (Compound Ia) from VIIIa
A jacketed glass vessel is charged with compound of formula VIIIa (1.0 equiv.) and methanol. The mixture is cooled with stirring to 10±5° C. and over the course of 20 minutes an aqueous solution of sodium hydroxide (3 equiv.) is charged. The mixture is aged with stirring at 20±5° C. for NLT
2 hours at which point the reaction is complete. Stirring is stopped and water is added. Methanol is then removed by vacuum distillation at an internal temperature of NMT
35° C. The resulting concentrated, clear aqueous solution is cooled to 10° C. and concentrated HCl is added until the pH was lowered to between 1.4-1.6 (pH meter) to precipitate the HCl salt. The solids are collected by filtration, washed with 0.2 N HCl and dried under vacuum at 50° C. to give a compound of Formula Ia in NLT 99.5% purity.Example 10Preparation of 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid (compound of formula IX) from VIIIa
Methyl 3-(3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoate (Compound of formula VIIIa) and methanol were charged into a vessel and the resulting mixture was agitated at 20±5° C. until dissolved. The solution was cooled to 10±5° C. and over the course of 20 minutes a sodium hydroxide solution was added while maintaining a temperature ≤25° C. The mixture temperature was adjusted to 25±5° C. and aged with stirring for 18 hours. The reaction mixture was filtered. Water was added to filtrate and the resulting mixture concentrated under vacuum until volume of the mixture was reduced to minimal volume. Water was again added and the resulting mixture concentrated under vacuum until volume of the mixture was reduced to minimal volume. The pH of the aqueous mixture was adjusted to 5.5±0.5 by addition of concentrated hydrochloric acid then 0.5N HCl. The temperature of the mixture was adjusted to 7±5° C. and aged with stirring for an additional hour. The solids were collected by filtration, washed with water and partially dried under vacuum at ≥55° C. to provide compound of Formula IX as white solids with >99.5% HPLC purity.Example 11Conversion of the Hydrochloride Salt to Free Base
3-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-propoxy]-4-fluorobenzoic acid hydrochloride (10.0 g, 30.4 mmol, 1.0 equiv.) was taken in deionized water (30.0 mL) at room temperature and was cooled to 10±5° C. To this mixture was added saturated sodium bicarbonate to pH≅6-7 and stirred for 30 minute at this temperature. The off white precipitate obtained was filtered and washed with deionized water (20 mL). Solid compound was dried at room temperature to afford 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-propoxy]-4-fluorobenzoic acid (the compound of Formula IX) (7.40 g, 83.2%) as an off-white solid.
Medical uses
Acoramidis is indicated for the treatment of the cardiomyopathy of wild-type or variant transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular death and cardiovascular-related hospitalization.[1][6][10]
ATTR-CM is a rare and serious disease that affects the heart muscle.[6] In people with ATTR-CM, there is a build-up of protein deposits in the heart, causing the walls of the heart to become stiff, and making the left ventricle unable to properly relax and fill with blood (called cardiomyopathy).[6] As the condition progresses, the heart can become unable to pump blood out adequately, causing heart failure.[6] There are two types of ATTR-CM, hereditary ATTR-CM (hATTR-CM) and wild-type ATTR-CM (wATTR-CM).[6] In hATTR-CM, which can run in families, there’s a variant in the transthyretin gene, which results in protein deposits in the heart. In wATTR-CM, there is no variant in the transthyretin gene.[6]
Side effects
The most common side effects are diarrhea and abdominal pain.[11]
History
The efficacy and safety of acoramidis were evaluated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult participants with wild-type or hereditary (variant) ATTR-CM (NCT03860935).[6]
Clinical trials
Phase I data indicated acoramidis achieved near-complete (>90%) TTR stabilization across the entire dosing interval at steady state.[12]
Phase II and the Open-Label Extension (OLE) data indicated after a median of 38 months, long-term treatment with acoramidis was generally well tolerated and resulted in a median decline in NT-proBNP levels, normalization of serum TTR, and sustained stabilization of TTR in individuals with ATTR-CM. [13]
Phase III data from ATTRibute-CM indicated acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo at 30 months in participants with ATTR-CM. Adverse events were similar in the two groups.[14]
Other analyses from ATTRibute-CM indicated a 50% reduction in cumulative cardiovascular hospitalizations (CVH), a 42% reduction in all-cause mortality (ACM) and recurrent CVH, and a 3-month time-to-separation of the Kaplan Meier curves for ACM or CVH. No other treatment has demonstrated this degree of treatment effect this quickly in participants with ATTR-CM.[15][16][17]
In vitro data indicated acoramidis exhibits near-complete (>90%) TTR stabilization at therapeutic trough concentrations, and its TTR stabilization exceeds that of tafamidis’ across a range of destabilizing TTR mutations.[18]
Society and culture
Legal status
Acoramidis was approved for medical use in the United States in November 2024.[6][7][19] The approval was granted to BridgeBio Pharma.[10]
In December 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Beyonttra, intended for the treatment of transthyretin amyloidosis in adults with cardiomyopathy.[2] The applicant for this medicinal product is BridgeBio Europe B.V.[2] Acoramidis was designated an orphan medicine by the EMA.[2] Acoramidis was authorized for medical use in the European Union in February 2025.[2][3]
Names
During development, acoramidis was known as AG10 (the Alhamadsheh-Graef molecule 10).[20]
Acoramidis is the international nonproprietary name.[21]
Acoramidis is sold under the brand names Attruby[1][6] and Beyonttra.[2][3]
References
- ^ Jump up to:a b c d e “Attruby- acoramidis hydrochloride tablet, film coated”. DailyMed. 26 November 2024. Retrieved 28 November 2024.
- ^ Jump up to:a b c d e f g “Beyonttra EPAR”. European Medicines Agency (EMA). 12 December 2024. Retrieved 15 December 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b c d “Beyonttra PI”. Union Register of medicinal products. 11 February 2025. Retrieved 16 February 2025.
- ^ Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, et al. (June 2013). “AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin”. Proceedings of the National Academy of Sciences of the United States of America. 110 (24): 9992–9997. Bibcode:2013PNAS..110.9992P. doi:10.1073/pnas.1300761110. PMC 3683741. PMID 23716704.
- ^ Miller M, Pal A, Albusairi W, Joo H, Pappas B, Haque Tuhin MT, et al. (September 2018). “Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis”. Journal of Medicinal Chemistry. 61 (17): 7862–7876. doi:10.1021/acs.jmedchem.8b00817. PMC 6276790. PMID 30133284.
- ^ Jump up to:a b c d e f g h i j k “FDA approves drug for heart disorder caused by transthyretin-mediated”. U.S. Food and Drug Administration. 1 October 2024. Retrieved 27 November 2024. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
- ^ “FDA approves BridgeBio Pharma’s Attruby to treat rare heart disease ATTR-CM”. PMLiVE. 25 November 2024. Retrieved 25 November 2024.
- ^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
- ^ Jump up to:a b LeMieux J (25 November 2024). “Bridgebio’s Attruby, to Treat Heart Condition ATTR-CM, Receives FDA Approval”. Genetic Engineering and Biotechnology News. Retrieved 25 November 2024.
- ^ “FDA approves BridgeBio’s Attruby for ATTR-CM treatment”. Pharmaceutical Technology. 25 November 2024. Retrieved 25 November 2024.
- ^ Fox JC, Hellawell JL, Rao S, O’Reilly T, Lumpkin R, Jernelius J, et al. (January 2020). “First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers”. Clinical Pharmacology in Drug Development. 9 (1): 115–129. doi:10.1002/cpdd.700. PMC 7003869. PMID 31172685.
- ^ Masri A, Aras M, Falk RH, Grogan M, Jacoby D, Judge DP, et al. (March 2022). “Long-Term Safety and Tolerability of Acoramidis (Ag10) in Symptomatic Transthyretin Amyloid Cardiomyopathy: Updated Analysis from an Ongoing Phase 2 Open-Label Extension Study”. Journal of the American College of Cardiology. 79 (9): 227. doi:10.1016/S0735-1097(22)01218-9.
- ^ Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, et al. (January 2024). “Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy”. The New England Journal of Medicine. 390 (2): 132–142. doi:10.1056/NEJMoa2305434. PMID 38197816.
- ^ “Program Planner”. http://www.abstractsonline.com. Archived from the original on 6 February 2021. Retrieved 19 October 2024.
- ^ Alexander K, Judge D, Cappelli F, Fontana M, Garcia-Pavia P, Grogan M, et al. (6 May 2024). Acoramidis Achieves Early Reduction in Cardiovascular Death or Hospitalization in Transthyretin Amyloid Cardiomyopathy (ATTR-CM): Results from the ATTRibute-CM Clinical Trial OC7 (#281) (Report). doi:10.26226/m.65f9bf8ae6f73964e1d4f069.
- ^ “BridgeBio Shares Recurrent Event Analysis of ATTRibute-CM, Demonstrating a 42% Reduction by Acoramidis on the Composite Endpoint of All-Cause Mortality and Recurrent Cardiovascular-related Hospitalization Events”. HFSA. Retrieved 19 October 2024.
- ^ Ji A, Wong P, Judge DP, Graef IA, Fox J, Sinha U (November 2023). “Acoramidis produces near-complete TTR stabilization in blood samples from patients with variant transthyretin amyloidosis that is greater than that achieved with tafamidis”. European Heart Journal. 44 (Supplement_2). doi:10.1093/eurheartj/ehad655.989. ISSN 0195-668X.
- ^ “Attruby (acoramidis), a Near Complete TTR Stabilizer (≥90%), approved by FDA to Reduce Cardiovascular Death and Cardiovascular-related Hospitalization in ATTR-CM Patients” (Press release). BridgeBio Pharma. 23 November 2024. Archived from the original on 25 November 2024. Retrieved 28 November 2024 – via GlobeNewswire.
- ^ “FDA approves Stanford Medicine-developed drug that treats rare heart disease”. Stanford. 27 November 2024. Retrieved 29 November 2024.
- ^ World Health Organization (2024). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 38 (1). hdl:10665/378096.
Further reading
- Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, et al. (June 2013). “AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin”. Proceedings of the National Academy of Sciences of the United States of America. 110 (24): 9992–9997. Bibcode:2013PNAS..110.9992P. doi:10.1073/pnas.1300761110. PMC 3683741. PMID 23716704.
External links
- Clinical trial number NCT03860935 for “Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy (ATTRibute-CM)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Pronunciation | ə-corAM-i-dis |
| Trade names | Attruby, others |
| Other names | AG10 |
| AHFS/Drugs.com | Monograph |
| License data | US DailyMed: Acoramidis |
| Routes of administration | By mouth |
| Drug class | Amyloidogenesis suppressant |
| ATC code | C01EB25 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1]EU: Rx-only[2][3] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1446711-81-42242751-53-5 |
| PubChem CID | 7146471371464713 |
| IUPHAR/BPS | 135307127 |
| DrugBank | DB17999 |
| ChemSpider | 35033544 |
| UNII | T12B44A1OEVY9C88C2NV |
| KEGG | D11972D11973 |
| ChEMBL | ChEMBL3940890ChEMBL4650226 |
| PDB ligand | 16V (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C15H17FN2O3 |
| Molar mass | 292.310 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- Nuvolone M, Girelli M, Merlini G: Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy. Int J Mol Sci. 2022 Dec 18;23(24):16145. doi: 10.3390/ijms232416145. [Article]
- Penchala SC, Connelly S, Wang Y, Park MS, Zhao L, Baranczak A, Rappley I, Vogel H, Liedtke M, Witteles RM, Powers ET, Reixach N, Chan WK, Wilson IA, Kelly JW, Graef IA, Alhamadsheh MM: AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9992-7. doi: 10.1073/pnas.1300761110. Epub 2013 May 28. [Article]
- Fox JC, Hellawell JL, Rao S, O’Reilly T, Lumpkin R, Jernelius J, Gretler D, Sinha U: First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers. Clin Pharmacol Drug Dev. 2020 Jan;9(1):115-129. doi: 10.1002/cpdd.700. Epub 2019 Jun 6. [Article]
- FDA Approved Drug Products: Attruby (acoramidis) tablets for oral administration (November 2024) [Link]
- FDA News Release: FDA approves drug for heart disorder caused by transthyretin-mediated amyloidosis [Link]
/////////Acoramidis, Attruby, AG 10, AG10. AG-10, WHO 11205, APPROVALS 2024, FDA 2024
Fitusiran
Fitusiran
1711.0 g/mol, C78H139N11O30
FDA APPROVED 3/28/2025, Qfitlia, To prevent or reduce the frequency of bleeding episodes in hemophilia A or B
Press Release
- CAS 1499251-18-1
- EX-A12034
- DA-53206
- N-[1,3-Bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]-12-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-12-oxododecanamide
Fitusiran Sodium
43 Sodium salt of duplex of [(2S,4R)-1-{1-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]-16,16-bis({3-[(3-{5-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]pentanamido}propyl)amino]-3-oxopropoxy}methyl)-5,11,18-trioxo-14-oxa-6,10,17-triazanonacosan-29-oyl}-4-hydroxypyrrolidin-2-yl]methyl hydrogen all–P–ambo-2′-deoxy-2′-fluoro-P-thioguanylyl-(3’→5′)-2′-O-methyl-P-thioguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methylcytidylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoro-3′-adenylate and all–P–ambo-2′-O-methyl-P-thiouridylyl-(3’→5′)-2′-deoxy-2′-fluoro-P-thiouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroguanylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyl-P-thiocytidylyl-(3’→5′)-2′-O-methyl-P-thioadenylyl-(3’→5′)-2′-O-methylguanosine
C520H636F21N175Na43O309P43S6 : 17193.39
[1609016-97-8]
Fitusiran, sold under the brand name Qfitlia, is a medication used for the treatment of hemophilia.[1] It is an antithrombin-directed small interfering ribonucleic acid.[1] It is given by subcutaneous injection.[1] Fitusiran reduces the amount of a protein called antithrombin.[2]
The most common side effects include viral infection, common cold symptoms (nasopharyngitis) and bacterial infection.[2]
Fitusiran was approved for medical use in the United States in March 2025.[2]
PATENT
https://patents.google.com/patent/WO2023240199A2/en
Medical uses
Fitusiran is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people aged twelve years of age and older with hemophilia A or hemophilia B, with or without factor VIII or IX inhibitors (neutralizing antibodies).[1][2]
Adverse effects
The US Food and Drug Administration prescription label for fitusiran contains a boxed warning for thrombotic events (blood clotting) and gallbladder disease (with some recipients requiring gallbladder removal).[2] The label also has a warning about liver toxicity and the need to monitor liver blood tests at baseline and then monthly for at least six months after initiating treatment with fitusiran or after a dose increase of fitusiran.[2]
History
The efficacy and safety of fitusiran were assessed in two multicenter, randomized clinical trials which enrolled a total of 177 adult and pediatric male participants with either hemophilia A or hemophilia B.[2] In one study, participants had inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with medicines known as “bypassing agents” for bleeding.[2] In the second study, participants did not have inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with clotting factor concentrates.[2] In the two randomized trials, participants received either a fixed dose of fitusiran monthly or their usual on-demand treatment (bypassing agents or clotting factor concentrates) as needed for nine months.[2] The fixed dose of fitusiran is not approved because it led to excessive clotting in some participants.[2]
The US Food and Drug Administration (FDA) granted the application for fitusiran orphan drug and fast track designations. The FDA granted the approval of Qfitlia to Sanofi.
Society and culture
Legal status
Fitusiran was approved for medical use in the United States in March 2025.[2][3]
Names
Fitusiran is the international nonproprietary name.[4]
Fitusiran is sold under the brand name Qfitlia.[1][2]
References
^ Jump up to:a b c d e f “Qfitlia- fitusiran injection, solution”. DailyMed. 26 March 2025. Retrieved 2 April 2025.
- ^ Jump up to:a b c d e f g h i j k l m “FDA Approves Novel Treatment for Hemophilia A or B, with or without Factor Inhibitors”. U.S. Food and Drug Administration. 28 March 2025. Retrieved 29 March 2025. This article incorporates text from this source, which is in the public domain.
- ^ “Qfitlia approved as the first therapy in the US to treat hemophilia A or B with or without inhibitors”. Sanofi (Press release). 28 March 2025. Retrieved 29 March 2025.
- ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1). hdl:10665/331046.
Further reading
Srivastava A, Rangarajan S, Kavakli K, Klamroth R, Kenet G, Khoo L, et al. (May 2023). “Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial”. The Lancet. Haematology. 10 (5): e322 – e332. doi:10.1016/S2352-3026(23)00037-6. PMID 37003278.
- Young G, Kavakli K, Klamroth R, Matsushita T, Peyvandi F, Pipe SW, et al. (March 2025). “Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study”. Blood. doi:10.1182/blood.2024027008. PMID 40053895.
- Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, et al. (April 2023). “Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial”. Lancet (London, England). 401 (10386): 1427–1437. doi:10.1016/S0140-6736(23)00284-2. PMID 37003287.
External links
- Clinical trial number NCT03417102 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors (ATLAS-INH)” at ClinicalTrials.gov
- Clinical trial number NCT03417245 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors” at ClinicalTrials.gov
- Clinical trial number NCT03754790 for “Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX (ATLAS-OLE)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Qfitlia |
| Other names | ALN-AT3SC |
| License data | US DailyMed: Fitusiran |
| Routes of administration | Subcutaneous |
| Drug class | Anthithrombin production inhibitor |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| CAS Number | 1499251–18–1 |
| DrugBank | DB15002 |
| UNII | SV9W47ZLE1 |
| KEGG | D11810 |
| Chemical and physical data | |
| Formula | C520H636F21N175Na43O309P43S6 |
| Molar mass | 17193.48 g·mol−1 |
////////Fitusiran, Qfitlia, FDA 2025, APPROVALS 2025, EX-A12034, DA-53206
New Drug Approvals 
