FLAGS AND HITS
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
FACEBOOK
...................................................................Join me on twitter
..................................................................Join me on google plus
GoogleplusMYSELF
Redafamdastat
Redafamdastat
cas 1020315-31-4, PF 04457845
JZP-150; JZP150; PF-04457845; PF-4457845; PF04457845; PF4457845, Q7119045
WeightAverage: 455.441
Monoisotopic: 455.156909393
Chemical FormulaC23H20F3N5O2
- 1-Piperidinecarboxamide, N-3-pyridazinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methylene]-
- N-pyridazin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methylidene]piperidine-1-carboxamide
Redafamdastat (INNTooltip International Nonproprietary Name; developmental code names JZP-150, PF-04457845) is an inhibitor of the enzyme fatty acid amide hydrolase (FAAH), with an IC50Tooltip half-maximal inhibitory concentration of 7.2 nM, and both analgesic and anti-inflammatory effects in animal studies comparable to those of the cyclooxygenase inhibitor naproxen.[1] It was being developed by Jazz Pharmaceuticals for the treatment of alcoholism, pain, and post-traumatic stress disorder (PTSD) and reached phase 2 clinical trials.[2][3] However, development of the drug was discontinued in December 2023.[2]
SCHEME
PAPER
ACS Medicinal Chemistry Letters (2011), 2(2), 91-96 86%
PATENT
WO2008047229 86%
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2008047229&_cid=P11-MCY7EC-33944-1
Example 1a
Synthesis of N-pyridin-3-yl-4-(3-(f5-(trifluoromethyl)pyridin-2-ylloxy)benzylidene)piperidine-1-carboxamide
Phenyl pyridin-3-ylcarbamate
To a stirred solution of 3-aminopyridine (51.7 g, 0.549 moles) in THF (900 mL) at -10 0C was added pyridine (52.1 g, 0.659 moles) in a stream over a 10 min period, followed by the dropwise addition of phenyl chloroformate (90 g, 0.575 moles) over a 20 min period. The reaction tempature increased to 5 0C. A precipitate formed during the addition. The resulting suspension was stirred at temperatures reaching ambient temperature over the next 3 h. The reaction mixture was partitioned between water (2 L) and EtOAc (1.5 L). The aqueous portion was extracted with EtOAc (1 L). The combined organic portions were dried (MgSO4) and concentrated in vacuo to a damp solid residue. This was suspended in
EtOAc:ether (1 :1 , 600 ml_). The resulting suspension was stirred at -10 0C for 2 h and filtered. The solid was rinsed with EtOAσether (1 :1 , 100 ml.) and pressed dry under suction. Further drying in vacuo at 35 0C for 7 h provided 104 g (88%) of product. Analysis, Calcd for Ci2H10N2O2: C, 67.28; H, 4.71 ; N, 13.08. Found: C, 67.15; H, 4.76; N, 12.87.
Step i
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol
3-Hydroxymethyl-phenol (5.00 g, 40.3 mmol, from Lancaster Synthesis), 2-chloro-5-trifluoromethyl-pyridine (7.31 g, 40.3 mmol, from TCI America) and potassium carbonate (6.96 g, 50.3 mmol) were suspended in dimethylformamide (80 mL) and heated to 95 0C. After stirring for 16 h, the solvent was distilled off in vacuo at 65 0C, and a residue was partitioned between water and heptane/ethyl acetate (1 :1 ). The organic layer was separated and the aqueous was extracted again with heptane/ethyl acetate (1 :1 ). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by silica gel chromatography (10-60%, EtOAc:heptane) to afford the desired product (5.70 g, 53% yield) as a light yellow oil. 1H NMR (400 MHz, CDCI3) δ ppm 4.73 (s, 2 H) 7.02 (dt, J=8.66, 0.57 Hz, 1 H) 7.04 – 7.11 (m, J=8.06, 2.40, 0.50, 0.50 Hz, 1 H) 7.15 – 7.19 (m, 1 H) 7.25 (ddd, J=8.39, 1.60, 0.80 Hz, 1 H) 7.42 (t, J=7.87 Hz, 1 H) 7.90 (ddd, J=8.67, 2.55, 0.50 Hz, 1 H) 8.43 (td, J=1.68, 0.84 Hz, 1 H).
Step 2
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.68 g, 17.4 mmol), in
dichloromethane (46 mL), was cooled to 0 0C, and treated dropwise with thionyl chloride (1.40 mL, 19.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 30 rηjn. Toluene (10 mL) was added and the mixture was concentrated by evaporation to form a residue. The residue was evaporated again from toluene and dried under high vacuum to afford the desired product (4.88 g, 98% yield) as an oil. 1H NMR (400 MHz, CDCI3) δ ppm 4.60 (s, 2 H) 7.03 (d, J=8.70 Hz, 1 H) 7.11 (ddd, J=8.09, 2.35, 0.94 Hz, 1 H) 7.20 (t, J=2.03 Hz, 1 H) 7.26 – 7.31 (m, 1 H) 7.42 (t, J=7.88 Hz, 1 H) 7.91 (dd, J=8.67, 2.53 Hz, 1 H) 8.44 (dd, J=1.51 , 0.90 Hz, 1 H).
Step 3
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester
2-(3-Chloromethyl-phenoxy)-5-trifluoromethyl-pyridine (4.88 g, 17.0 mmol) from Step 2 was treated neat with triethylphosphite (4.36 mL, 25.4 mmol) and heated to 150 0C. After 6 h, the reaction mixture was cooled, treated with an additional 0.5 mL triethylphosphite (2.9 mmol) and reheated to 150 0C. After 6 h, the reaction mixture was removed from the heat and slowly treated with heptane (about 60 mL) while stirring to afford a white solid. The solid was collected by filtration, washed with heptane and dried in a vacuum oven for 16 h at 45 0C to afford a white powder (5.99 g, 91% yield). MS (APCI) M+1= 390.1 ; 1H NMR (400 MHz, CDCI3) δ ppm 1.26 (t, J=7.02 Hz, 6 H) 3.18 (d, J=21.83 Hz, 2 H) 3.99 – 4.10 (m, 4 H) 7.01 (d, J=8.58 Hz, 1 H) 7.03 – 7.08 (m, 1 H) 7.12 (q, J=2.21 Hz, 1 H) 7.19 – 7.24 (m, 1 H) 7.38 (t, J=7.90 Hz, 1 H) 7.90 (dd, J=8.58, 2.53 Hz, 1 H) 8.43 (dd, J=1.66, 0.88 Hz, 1 H).
Step 4
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1 -carboxylic acid tert-butyl ester
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (2.3 g, 6.0 mmol) from Step 3 and 1 ,4,7,10, IS-pentaoxacyclopentadecane (15-Crown-5, 0.03 ml_, 0.15 mmol) were combined in THF (10 ml_). The mixture was cooled to 0 °C and sodium hydride (240 mg, 60% dispersion in mineral oil, 6.0 mmol) was added. The reaction was warmed to room temperature, stirred for 30 minutes and then cooled back to 0 0C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 6.0 mmol) in THF (6 ml_) was added and the reaction was warmed to room temperature. After 16 hours, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2X200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to a thick oil. Treatment of the oil with hot isopropyl ether (45 mL) provided the title compound as a white solid (1.88 g). 1H NMR (400 MHz, CD3OD) δ ppm 1.46 (s, 9 H) 2.34 (td, J=5.85, 1.18 Hz, 2 H) 2.46 (td, J=5.87, 1.07 Hz, 2 H) 3.37 – 3.44 (m, 2 H) 3.45 – 3.57 (m, 2 H) 6.41 (s, 1 H) 6.92 – 7.04 (m, 2 H) 7.06 – 7.17 (m, 2 H) 7.31 – 7.54 (m, 1 H) 8.08 (ddd, J=8.74, 2.59, 0.56 Hz, 1 H) 8.42 (td, J=1.73, 0.90 Hz, 1 H).
Step 5
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride
4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 3.11 mmol) from Step 4 was dissolved in CH2CI2 (30 mL) and treated with HCI in diethyl ether (10 mL, 2.0 M, 20 mmol). After 16 hours the reaction was concentrated in vacuo to form a residue and the residue was suspended in acetonitrile (10 mL) to yield a solid. Filtration of the solid provided the title compound as a white solid (1.1 g). 1H NMR (400 MHz, CD3OD) δ ppm 2.62 (td, J=6.11 , 0.91 Hz, 2 H) 2.67 – 2.81 (m, 2 H) 3.14 – 3.21 (m, 2 H) 3.22 – 3.29 (m, 2 H) 6.56 (s, 1 H) 6.99 – 7.09 (m, 2 H) 7.10 – 7.18 (m, 2 H) 7.42 (t, J=7.91 Hz, 1 H) 8.09 (ddd, J=8.74, 2.60, 0.33 Hz, 1 H) 8.41 (td, J=1.63, 0.74 Hz, 1 H).
Step 6
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (800 mg, 2.16 mmol, from Step 5), phenyl pyridin-3-ylcarbamate (508 mg, 2.37 mmol) and diisopropylethylamine (0.75 mL, 4.52 mmol) were combined in acetonitrile (10 mL) and stirred at room temperature. After 16 hours, the reaction was concentrated forming a residue and the residue was partitioned between EtOAc and water. The organic layer was separated, washed with 5% NaOH (aq), dried over anhydrous sodium sulfate, filtered and concentrated. Treatment of the residue with hot isopropyl ether and purified from isopropyl ether/methanol provided the title compound as a white solid (574 mg). MS (APCI 10V) AP+ 455.3, 376.2, 335.2, AP- 453.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.46 (td, J=5.86, 0.97 Hz, 2 H) 2.58 (td, J=5.82, 1.16 Hz, 2 H) 3.51 – 3.60 (m, 2 H) 3.61 – 3.70 (m, 2 H) 6.46 (s, 1 H) 6.98 – 7.07 (m, 2 H) 7.09 – 7.19 (m, 2 H) 7.34 (ddd, J=8.41 , 4.81 , 0.65 Hz, 1 H) 7.40 (td, J=7.69, 0.74 Hz, 1 H) 7.91 (ddd, J=8.38, 2.58, 1.44 Hz, 1 H) 8.08 (ddd, J=8.73, 2.61 , 0.55 Hz, 1 H) 8.16 (dd, J=4.84, 1.06 Hz, 1 H) 8.43 (td, J=1.74, 0.91 Hz, 1 H) 8.58 (d, J=1.88 Hz, 1 H).
Example 1b
Large scale synthesis of N-pyridin-3-yl-4-(3-{[5-(trifluoromethyl)pyridin-2-ylloxy)benzylidene)piperidine-1- carboxamide
Step 1 : Preparation of r3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyll-methanol
To a solution of S-trifluoromethyl^-chloro-pyridine (150.0 g, 0.826 mol) in DMF (1.9 L) was added 3-hydroxy-phenyl-methanol (112.5 g, 0.906 mol) and of potassium carbonate (171.0 g, 1.237 mol). The solids were washed into the flask with 100 mL of DMF. The stirred mixture was heated to 95-105 0C for 5 h. It was cooled to ambient temperature and then poured into 5 L of stirred ice-water. The mixture was extracted with etheπhexane (2:1 , 1.5 L, 1.0 L). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to dryness to give the product (222.5 g, 100%).
Step 2: Preparation of 2-(3-chloromethyl-phenoxy)-5-trifluoromethylpyridine
To a solution of [3-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol (281.0 g, 1.044 moles) in dichloromethane (2.0 L) at -5 0C was added dropwise over a 25 min period thionyl chloride (136.6 g, 1.148 mol). A few minutes into the addition, a white substance separated but this went into solution several minutes later. The reaction was stirred at ambient temperature for 1 h and then was concentrated in vacuo to near dryness (357 g). 200 mL of toluene was added to the residue and the solution was again concentrated in vacuo to near dryness. 200 mL of toluene was added and some solid (-8 g) was filtered off. The filtrate was concentrated in vacuo to -390 g of dark yellow liquid.
Step 3: Preparation of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyll-phosphonic acid diethyl ester
A solution of 2-(3-chloromethyl-phenoxy)-5-trifluoromethylpyridine (-298 g, -1.036 mol) containing some toluene in triethyl phosphite (267.0 g, 1.551 mol) was heated to 135 °C-140 0C for 7 h. Boiling began at -110 0C and continued throughout the reaction. The solution was left standing at ambient temperature overnight and it solidified. The solid was suspended in etheπhexane (1 :2, 450 mL), and the suspension was stirred at ambient temperature for 3 h and filtered. The solid was rinsed with etherhexane (1 :2, 150 mL) and pressed dry under suction. Further drying in vacuo at 32 0C for 7 h provided 286.3 g (71 % – 2 steps from crude chloride) of product. The filtrate was concentrated in vacuo to remove the low boiling solvents. Triethyl phosphite (36.0 g, 0.217 mol) was added and the solution was heated to 130 0C for 2 h. The reaction was cooled to 100 0C and 300 mL of heptane was added slowly. A solid separated. As the temperature decreased to -30 0C, 150 mL of ether was added. The resulting suspension was left standing at ambient temperature overnight and was filtered. The solid was rinsed with etherheptane (1 :2, 75 mL) and pressed dry under suction. Further drying in vacuo at 32 0C for 7 h afforded and additional 35.7 g (9%) of product. Total yield = 322 g (80%). Anal. Calcd for C17H19 F3NO4P (389.31 ) : C, 52.45; H, 4.92; N, 3.60; F, 14.64; P, 7.96. Found : C, 52.73; H, 5.04; N, 3.58; F, 14.35; P, 7.74; chloride, <0.10%.
Step 4: Preparation of 4-f3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidenel-piperidine-1-carboxylic acid tert-butyl ester
To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at -10 0C was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to -3 °C during the addition. The resulting red mixture was stirred between -6 0C and -10 0C for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2 0C. The resulting red mixture was stirred at temperatures reaching 21 0C over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at -10 0C for 2 h and filtered. Drying in vacuo at 25 CC for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at -10 0C for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl etherheptane (1 :3) and pressed dry under suction. Further drying in vacuo at 34 °C for 6 h provided an additional 34.2 g (19.5%) of product. Total yield = 119.2 g (68.5%).
Step 5: Preparation of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine, hydrochloride
To a mixture of 4-[3-(5-trifluoromethyl-pyridin-2-yloxy)-benzylidene]-piperidine-1-carboxylic acid fert-butyl ester (312 g, 0.718 mol) in ethyl acetate (2.8 L) at 0 0C to -5 0C was added streamwise over a 20 min period, 4.0 M hydrogen chloride in dioxane (800 mL, 3.2 mol). No significant temperature change was noted. The resulting suspension was stirred at temperatures reaching 22 0C over the next 17 h. The suspension was filtered. The solid was washed with EtOAc (500 mL) and pressed as dry as possible under suction. The damp solid was dried in vacuo at 33 0C for 7 h to afford 225 g (84%) of product.
Step 6: Preparation of N-pyridin-3-yl-4-(3-(f5-(trifluoromethyl)pyridin-2-ylloxy}benzylidene)piperidine-1-carboxamide
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine (80.0 g, 0.216 mol) and phenyl pyridin-3-ylcarbamate (48.6 g, 0.227 mol) in acetonitrile (650 mL) was added dropwise diisopropylethyl amine (55.8 g, 0.432 mol). A solution formed after -45 min of stirring. The slightly turbid solution was stirred at ambient temperature for 18 h. TLC showed a prominent product spot with traces of both starting materials and two other fast moving spots. The solution was concentrated in vacuo to a viscous oil. This was partitioned between dichloromethane (600 mL) and water (500 mL). The aqueous layer was extracted with 200 mL of dichloromethane. The combined organic layers were washed with successive portions of 500 mL of 5% sodium hydroxide, and 200 mL of water, then dried over magnesium sulfate and concentrated in vacuo to 139.5 g of a viscous oil. This was dissolved in 350 ml_ of warm (50 0C) methyl t-butyl ether. Soon after a solution formed, solid began separating. The crystallizing mixture was kept at -10 0C for 4 h and filtered. The solid was rinsed with 60 ml_ of methyl t-butyl ether and pressed dry under suction. Further drying in vacuo at 28 0C for 16 h and then at 35 °C for 6 h provided 93.2 g (95%) of product.
PAPER
ACS Medicinal Chemistry Letters (2011), 2(2), 91-96
https://pubs.acs.org/doi/10.1021/ml100190t
PAPER
Science (Washington, DC, United States) (2017), 356(6342), 1084-1087
Pfizer Products Inc.WO2008047229
References
- ^ Johnson DS, Stiff C, Lazerwith SE, Kesten SR, Fay LK, Morris M, et al. (February 2011). “Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor”. ACS Medicinal Chemistry Letters. 2 (2): 91–96. doi:10.1021/ml100190t. PMC 3109749. PMID 21666860.
- ^ Jump up to:a b “JZP 150”. AdisInsight. 26 December 2023. Retrieved 16 August 2024.
- ^ “A Study of JZP150 in Adults With Posttraumatic Stress Disorder – Full Text View – ClinicalTrials.gov”. clinicaltrials.gov.
- [1]. Johnson DS, et al. Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor. ACS Med Chem Lett. 2011 Feb 10;2(2):91-96. [Content Brief][2]. Ahn K, et al. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain. J Pharmacol Exp Ther. 2011 Jul;338(1):114-24. [Content Brief][3]. Buntyn RW, et al. Inhibition of Endocannabinoid-Metabolizing Enzymes in Peripheral Tissues Following Developmental Chlorpyrifos Exposure in Rats. Int J Toxicol. 2017 Jan 1:1091581817725272. [Content Brief]
////////Redafamdastat, PF 04457845, JZP-150, JZP150, PF-04457845, PF-4457845, PF04457845, PF4457845, Q7119045
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
join me on Linkedin
Anthony Melvin Crasto Ph.D – India | LinkedIn
join me on Researchgate
RESEARCHGATE
join me on Facebook
Anthony Melvin Crasto Dr. | Facebook
join me on twitter
Anthony Melvin Crasto Dr. | twitter
+919321316780 call whatsaapp
EMAIL. amcrasto@gmail.com
ARAZASETRON BESYLATE
ARAZASETRON BESYLATE
R-Azasetron besylate, SENS-401
Cas 2025360-91-0
C17H20ClN3O3.C6H6O3S, 507.99, UXP39EQ477
2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-, benzenesulfonate (1:1)
N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide; benzenesulfonic acid
X HCL SALT, CAS , 2139305-21-6, Name2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,…
BASE: 2025360-90-9
.HCL SALT CAS, 2566443-39-6
Name 2H-1,4-Benzoxazine-8-carboxamide, N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,…
BASE: 2025360-90-9
Base CHIRAL 2025360-90-9
- N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxamide
(R)-Azasetron besylate (SENS-401) is an orally active calcineurin inhibitor. (R)-Azasetron besylate reduces Cisplatin (HY-17394)-induced hearing loss and cochlear damage.
Arazasetron Besylate is the besylate salt form of the R-enantiomer of azasetron, a benzamide derivative and selective serotonin (5-hydroxytryptamine; 5-HT) receptor and calcineurin antagonist, with potential antinauseant and antiemetic, and otoprotective activities. Upon administration, arazasetron selectively binds to and inhibits 5-HT subtype 3 receptors (5-HT3R) located peripherally on vagus nerve terminals and centrally in the chemoreceptor trigger zone (CTZ) of the area postrema, which may result in suppression of nausea and vomiting. R-azasetron also targets and inhibits the activation of calcineurin, thereby preventing inner ear lesions, nerve degeneration, induction of apoptosis and sensory hair loss. This may prevent hearing loss. Calcineurin activation plays a key role in structural degeneration, swelling, synaptic uncoupling and the induction of apoptosis in the inner ear leading to hair cell loss and hearing loss.
SCHEME
PATENTS
WO2017178645
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017178645&_cid=P22-MCX71S-95827-1
PATENTS
US20190083503
https://patentscope.wipo.int/search/en/detail.jsf?docId=US239434911&_cid=P22-MCX73M-97768-1
PATENTS
WO2010/133663
CN101786963
CN104557906
WO201717864
WO2021014014
WO2023175078
WO2023122719
Base WO2017178645
WO2021014014
WO2023175078
//////////ARAZASETRON BESYLATE, R-Azasetron besylate, UXP39EQ477, SENS-401, SENS 401
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.
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
join me on Linkedin
Anthony Melvin Crasto Ph.D – India | LinkedIn
join me on Researchgate
RESEARCHGATE
join me on Facebook
Anthony Melvin Crasto Dr. | Facebook
join me on twitter
Anthony Melvin Crasto Dr. | twitter
+919321316780 call whatsaapp
EMAIL. amcrasto@gmail.com
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
PRITELIVIR MESYLATE
PRITELIVIR MESYLATE
CAS 1428333-96-3
1428321-10-1 HYDRATE
FREE FORM
AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate
BAY57-1293; BAY 57-1293; BAY-57-1293; BAY571293; BAY 571293; BAY-571293; AIC-316; AIC 316
| Molecular Weight | 516.61 |
|---|---|
| Synonyms | AIC316 mesylate hydrate; BAY 57-1293 mesylate hydrate |
| Formula | C19H24N4O7S3 |
| CAS No. | 1428321-10-1 |
Pritelivir mesylate is an antiviral drug currently under development, specifically targeting herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). It functions by inhibiting the viral helicase-primase enzyme, a crucial component for HSV replication. It is being investigated as a potential treatment for various herpes infections, including those resistant to traditional antivirals like acyclovir.
Key aspects of Pritelivir mesylate:
- Mechanism of Action:Pritelivir is a helicase-primase inhibitor, meaning it blocks the activity of an enzyme essential for the replication of herpes viruses.
- Target Viruses:It is effective against both HSV-1 and HSV-2, the viruses responsible for cold sores and genital herpes, respectively.
- Potential for Resistance:Pritelivir has shown promise in preclinical studies against acyclovir-resistant strains of HSV, making it a potential alternative for patients with drug-resistant infections.
- Clinical Trials:Pritelivir is currently in phase II clinical trials, with ongoing research into its effectiveness and safety.
- Route of Administration:It is being investigated for oral, topical, and vaginal administration.
- Research and Development:Pritelivir is being developed by AiCuris Anti-infective Cures, building upon research from Bayer.
Pritelivir (development codes AIC316 or BAY 57-1293) is a direct-acting antiviral drug in development for the treatment of herpes simplex virus infections (HSV). This is particularly important in immune compromised patients. It is currently in Phase III clinical development by the German biopharmaceutical company AiCuris Anti-infective Cures AG. US FDA granted fast track designation for pritelivir in 2017 and breakthrough therapy designation 2020.
SCHEME
Pritelivir mesylate, an antiviral drug used to treat herpes simplex virus (HSV) infections, is synthesized through a series of chemical reactions, including palladium-catalyzed coupling, ester saponification, and amide coupling reactions. The mesylate salt is then formed by reacting the free base with methanesulfonic acid.
Detailed Synthesis Steps:
- 1. Diaryl Acetic Acid Synthesis:Diaryl acetic acid reagents are synthesized using palladium-catalyzed coupling reactions. These reactions involve the use of organometallic intermediates derived from halo-aryl esters.
- 2. Ester Saponification:The ester group in the synthesized compounds is then converted to a carboxylic acid group through saponification.
- 3. Amide Coupling:The resulting carboxylic acids are coupled with thiazolyl sulfonamides using amide coupling conditions to form the pritelivir molecule.
- 4. Salt Formation:The pritelivir free base is then reacted with methanesulfonic acid to form the mesylate salt, which is the active pharmaceutical ingredient (API).
Key Aspects of Pritelivir Mesylate Synthesis:
- Targeted Mechanism:Pritelivir mesylate inhibits the herpes simplex virus by targeting the viral helicase-primase complex, essential for DNA replication, unlike traditional antivirals that target DNA polymerase.
- Salt and Polymorph Screening:An extensive salt and polymorph screening is performed to optimize the pharmaceutical development of pritelivir, resulting in various salt forms including the mesylate, maleate, and sulfate.
- Solubility and Stability:Pritelivir mesylate is a BCS Class II drug substance with pH-dependent solubility. It exhibits high solubility below pH 3 and poor solubility at neutral pH.
- Formulation Considerations:Due to its limited water solubility, pritelivir mesylate is often formulated with solvents like DMSO, PEG300, Tween-80, and saline or with cyclodextrins like SBE-β-CD.
- Clinical Trials:Pritelivir mesylate is currently under extensive study to evaluate its efficacy and safety profile, with promising results in early clinical trials.
PATENT
WO2018096170
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018096170&_cid=P20-MCVCP5-34284-1
PATENT
WO2018096177
PATENT
https://patents.google.com/patent/WO2018096177A1/en
Likewise, EP 2 598 502 Al describes the crystalline mono mesylate monohydrate salt of N- [5-(aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetar^ in a definite particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said N-[5- (aminosulfonyl)-4-methyl- 1 ,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide mono mesylate monohydrate having the afore-mentioned particle size distribution and specific surface area range.
WO 2013/045479 Al describes an improved and shortened synthesis process of N-[5- (ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetaniide and the mesylate salt thereof by using boronic acid derivatives or borolane reagents while avoiding toxic organic tin compounds. Moreover, also the crystalline mesylate monohydrate salt of N- [5 -(aminosulfonyl)-4-methyl- 1 ,3 -thiazol-2-yl] -N-methyl-2- [4-(2-pyridinyl)-phenyl] – acetamide is described therein with increased long-term stability and release kinetics from pharmaceutical compositions thereof.
Said pritelivir is an innovative, highly active and specific inhibitor of herpes simplex virus (HSV) infections. As a compound derived from the chemical class of thiazolylamides, pritelivir is active against both types of herpes simplex virus causing labial and genital herpes, respectively, and retains activity against viruses which have become resistant to marketed drugs. Pritelivir has a mode of action that is distinct from other antiviral agents currently in use for treatment of HSV infections (i.e., the nucleoside analogues acyclovir and its prodrug valacyclovir as well as famciclovir, the prodrug of penciclovix). Whereas nucleoside analogs terminate ongoing DNA chain elongation through inhibition of viral DNA polymerase, pritelivir prevents de novo synthesis of virus DNA through inhibition of the helicase-primase complex. In addition, it does not require activation within an HSV infected cell by viral thymidine kinase and therefore, is also protective to uninfected cells.
With the context of the invention, similar expressions which all would denote the compound pritelivir are “BAY 57-1293”, “AIC090096” and “AIC316”.
Likewise, the terms ”pritelivir”, “BAY 57-1293”, “AIC090096” and “AIC316″ or the compound *’N-[5-(ammosulfonyl)-4-methyl-l,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridm phenyl] -acetamide” would reflect throughout the text a compound having the structural formula:
Synthetic route – Manufacture of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-Yl]-N-methyl- 2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate
The starting materials (4-pyridine-2-yl-phenyl)-acetic acid (PP-acetic acid; C-023930) and aminothiazole sulfonic acid amide (C-023936) are coupled using standard reaction conditions
(N-Ethyl-N’-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC x HCl), tetrahydrofuran (THF)/N-methylpyrrolidone (NMP) to deliver N-[5-(aminosulfonyl)-4- methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate (C-023931). To obtain the hemihydrate, N-[5-(aminosulfonyl)-4-methyl-1,3- thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate free base is recrystallized from THF/water. A flowchart showing the synthesis of N-[5-(aminosulfonyl)- 4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide is provided in below in the reaction scheme below 1.
Description of the manufacturing process of N-r5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide free base hemihydrate
PP-acetic acid and aminothiazole sulfonic acid amide are mixed in THF/NMP, the mixture is cooled and then EDC x HCl is added in portions. The reaction mixture is stirred for several hours, and then added slowly to purified water. The suspension is stirred and filtered; the product cake is washed with purified water and dried at room temperature in a nitrogen stream and then under vacuum. Purified water is added slowly at elevated temperature, the suspension is stirred for several hours. The suspension is cooled to 5°C and stirred further for several hours. The product is isolated by filtration and washed with purified water. The product is dried at 65°C under vacuum until the criterion for water content is reached. A major advantage of the synthesis of free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide hemihydrate is the absence impurities related to the presence of mesylate ester that might be present in the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamide mesylate.
PAPER
By: Carta, Fabrizio ; et al. Journal of Medicinal Chemistry (2017), 60(7), 3154-3164
SULPHURIC ACID FOR SULPHATE A SIMILAR REACTION BUT NOT SAME
PAPER
https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00668
Chemistry of Pritelivir
Synthesis of pritelivir and its analogues is based on the reported methods in the literature (18−20) and presented in Figure 4. A simple retrosynthetic disconnection of the target compound suggests a coupling of the thiazolyl sulfonamide and diaryl acetic acid (Figure 4a). During the course of development an optimized route applying the principles of green chemistry was developed and will be used for the commercial phase.
Figure 4. Synthesis of pritelivir (16) and analogues: (a) disconnection approach to target molecules; (b) synthesis of thiazolyl sulfonamide reagents; (c) synthesis of diaryl acetic acids; (d) synthesis of some representative examples of pritelivir and analogues. (18−20)
The synthesis of the thiazolyl sulfonamide reagents begins with a reaction of chloroacetone (17) and potassium thiocyanide to give an intermediate ketone which was cyclized to the thiazole 18 by treatment with gaseous hydrochloride (Figure 4b). Chlorosulfonylation with chlorosulfonic acid and thionyl chloride resulted in the sulfonyl chloride 19 that was converted to the corresponding sulfonamides 20 and 21 after treatment with ammonia or methylamine, respectively. The 2-chloro substituent in 20 and 21 was converted to the methyl amine in an SNAr reaction to deliver the building blocks 22–23. Diaryl acetic acid reagents were synthesized using palladium catalyzed coupling reactions with organometallic intermediates formed from the corresponding halo-aryl esters (Figure 4c). Ester saponification then delivered the corresponding carboxylic acids (e.g., 26 and 28, Figure 4c). Finally, the target molecules, for instance, 5, 11, 16, and 9, were obtained using amide coupling reaction conditions with corresponding diaryl acetic acids and the thiazolyl sulfonamides (Figure 4d). (18−20)
Medical use
Pritelivir is currently being developed for the treatment of immunocompromised patients with mucocutaneous HSV lesions that are resistant to acyclovir.
HSV in immunocompromised patients
Although HSV infection is very common in the general population, it rarely causes serious disease and is effectively contained by the immune system. In those with a weakened immune system such as transplant recipients, people receiving chemo- or radiotherapy, or HIV patients, an active HSV infection can cause disease in 35-68% of patients and may become severe or even life-threatening.[1]
Standard of care treatments
HSV treatment revolves around the use of nucleoside analogues (NA) which act via the viral DNA polymerase, causing DNA chain termination and prevention of viral replication. First-line treatment is generally acyclovir or its prodrug valacyclovir. Resistance to acyclovir is more common in HSV patients with weakened or suppressed immune systems, affecting between 4 and 25% of cases.[2][3][4][5][6]
Resistance to standard treatments
If HSV drug resistance is mediated by mutation(s) of the viral UL23 gene, which encodes the viral thymidine kinase (TK), then the pyrophosphate analogue foscarnet may be effective as a rescue treatment, since it does not require activation by TK. The use of foscarnet is commonly accompanied by restrictive toxicity, particularly nephrotoxicity.[7] If the virus also acquires resistance to foscarnet, then there is currently no FDA approved treatment.
Clinical research
Completed phase II clinical trials in otherwise healthy patients with genital herpes
- A Double-blind Randomized Placebo Controlled Dose-finding Trial to Investigate Different Doses of a New Antiviral Drug in Subjects With Genital HSV Type 2 Infection.[8][9]
- A Double-blind, Double Dummy, Randomized Crossover Trial to Compare the Effect of “AIC316 (Pritelivir)” 100 mg Once Daily Versus Valacyclovir 500 mg Once Daily on Genital HSV Shedding in HSV-2 Seropositive Adults.[10][11]
Ongoing phase II / phase III clinical trials with pritelivir
A phase II / III multinational, comparator-controlled, clinical trial in immunocompromised patients with acyclovir-resistant mucocutaneous lesions is listed on ClinicalTrials.gov[12] and EudraCT.[13]
Pharmacology
Mechanism of action
Pritelivir is a member of the helicase-primase inhibitors (HPI), a novel class of direct-acting antiviral drugs acting specifically against HSV-1 and HSV-2.[14][15] As the name suggests, the drugs act through inhibition of the viral helicase primase complex, encoded by the UL5 (helicase), UL8 (scaffold protein) and UL52 (primase) genes, which is essential for HSV replication.[16] The helicase primase complex is encoded separately from the viral DNA polymerase (encoded by the UL30 gene). Because HPIs i) do not target the viral DNA polymerase and ii) do not require activation by the viral thymidine kinase enzyme (encoded by the UL23 gene), mutations causing resistance to NAs are not protective against HPIs. Similarly, resistance to HPIs does not confer resistance to NAs.
References
- ^ Wilck, M.B.; Zuckerman, R.A.; A. S. T. Infectious Diseases Community of Practice (2013). “Herpes simplex virus in solid organ transplantation”. Am J Transplant. 13 (Suppl 4): 121–7. doi:10.1111/ajt.12105. PMID 23465005. S2CID 44969727.
- ^ Zuckerman, R.; Wald, A.; A. S. T. Infectious Diseases Community of Practice (2009). “Herpes simplex virus infections in solid organ transplant recipients”. Am J Transplant. 9 (Suppl 4): S104-7. doi:10.1111/j.1600-6143.2009.02900.x. PMID 20070669. S2CID 205846431.
- ^ Frobert, E.; Burrel, S.; Ducastelle-Lepretre, S.; Billaud, G.; Ader, F.; Casalegno, J.S. (2014). “Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France”. Antiviral Res. 111: 36–41. doi:10.1016/j.antiviral.2014.08.013. PMID 25218782.
- ^ Patel, D.; Marchaim, D.; Marcus, G.; Gayathri, R.; Lephart, P.R.; Lazarovitch, T.; Zaidenstein, R.; Chandrasekar, P. (2014). “Predictors and outcomes of acyclovir-resistant herpes simplex virus infection among hematopoietic cell transplant recipients: case-case-control investigation”. Clin Transplant. 28 (1): 1–5. doi:10.1111/ctr.12227. PMID 24033498. S2CID 37729458.
- ^ Danve-Szatanek, C.; Aymard, M.; Thouvenot, D.; Morfin, F.; Agius, G.; Bertin, I. (2004). “Surveillance network for herpes simplex virus resistance to antiviral drugs: 3-year follow-up”. J Clin Microbiol. 42 (1): 242–9. doi:10.1128/JCM.42.1.242-249.2004. PMC 321677. PMID 14715760.
- ^ Chakrabarti, R.; Pillay, D.; Ratcliffe, D.; Cane, P.A.; Collingham, K.E.; Milligan, D.W. (2000). “Resistance to antiviral drugs in herpes simplex virus infections among allogeneic stem cell transplant recipients: risk factors and prognostic significance”. J Infect Dis. 181 (6): 2055–8. doi:10.1086/315524. PMID 10837192.
- ^ SmPC
- ^ NCT01047540
- ^ Wald, A.; Timmler, B.; Magaret, A.; Warren, T.; Trying, S. (2014). “Helicase-primase inhibitor pritelivir for HSV-2 infection”. N Engl J Med. 370 (3): 201–10. doi:10.1056/NEJMoa1301150. PMID 24428466.
- ^ NCT01658826
- ^ Wald, A.; Timmler, B.; Warren, T.; Trying, S.; Johnston, C. (2016). “Effect of Pritelivir Compared With Valacyclovir on Genital HSV-2 Shedding in Patients With Frequent Recurrences: A Randomized Clinical Trial”. JAMA. 316 (23): 2495–2503. doi:10.1001/jama.2016.18189. hdl:1805/14200. PMID 27997653.
- ^ NCT03073967
- ^ 2020-004940-27
- ^ Biswas, S.; Jennens, L.; Field, H.J. (2007). “Single amino acid substitutions in the HSV-1 helicase protein that confer resistance to the helicase-primase inhibitor BAY 57-1293 are associated with increased or decreased virus growth characteristics in tissue culture”. Arch Virol. 152 (8): 1489–500. doi:10.1007/s00705-007-0964-7. PMID 17404685. S2CID 23688945.
- ^ Field, H.J.; Biswas, S. (2011). “Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus”. Drug Resist Updat. 14 (1): 45–51. doi:10.1016/j.drup.2010.11.002. PMID 21183396.
- ^ Crute, J.J.; Tsurumi, T.; Zhu, L.A.; Weller, S.K.; Olivo, P.D.; Challberg, M.D. (1989). “Herpes simplex virus 1 helicase-primase: a complex of three herpes-encoded gene products”. Proc. Natl. Acad. Sci. U.S.A. 86 (7): 2186–2189. Bibcode:1989PNAS…86.2186C. doi:10.1073/pnas.86.7.2186. PMC 286876. PMID 2538835.
- [1]. Ligat G, et al. Identification of Amino Acids Essential for Viral Replication in the HCMV Helicase-PrimaseComplex. Front Microbiol. 2018 Oct 23;9:2483. [Content Brief][2]. Wald A, et al. Helicase-primase inhibitor Pritelivir for HSV-2 infection. N Engl J Med. 2014 Jan 16;370(3):201-10. [Content Brief][3]. Quenelle DC, et al. Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis. Antiviral Res. 2018 Jan;149:1-6. [Content Brief]
| Names | |
|---|---|
| Systematic IUPAC nameN-Methyl-N-(4-methyl-5-sulfamoyl-1,3-thiazol-2-yl)-2-[4-(pyridin-2-yl)phenyl]acetamide | |
| Identifiers | |
| CAS Number | 348086-71-5 |
| 3D model (JSmol) | Interactive image |
| ChemSpider | 430613 |
| KEGG | D12811 |
| PubChem CID | 491941 |
| UNII | 07HQ1TJ4JE |
| CompTox Dashboard (EPA) | DTXSID70188344 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C18H18N4O3S2 |
| Molar mass | 402.49 g·mol−1 |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).Infobox references | |
///////////PRITELIVIR MESYLATE, AIC316 mesylate hydrate, BAY 57-1293 mesylate hydrate, AIC 316 mesylate hydrate, BAY 57-1293 mesylate hydrate, BAY57-1293, BAY 57-1293, BAY-57-1293, BAY571293, BAY 571293, BAY-571293, AIC-316, AIC 316
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
join me on Linkedin
Anthony Melvin Crasto Ph.D – India | LinkedIn
join me on Researchgate
RESEARCHGATE
join me on Facebook
Anthony Melvin Crasto Dr. | Facebook
join me on twitter
Anthony Melvin Crasto Dr. | twitter
+919321316780 call whatsaapp
EMAIL. amcrasto@gmail.com
PIMICOTINIB
PIMICOTINIB
CAS 2253123-16-7
ABSK021
WeightAverage: 420.473
Monoisotopic: 420.190988657
Chemical FormulaC22H24N6O3
3,3-dimethyl-N-[6-methyl-5-[2-(1-methylpyrazol-4-yl)pyridin-4-yl]oxypyridin-2-yl]-2-oxopyrrolidine-1-carboxamide
CSF-1R inhibitor Pimicotinib (ABSK021) of Abbisko Therapeutics, HV1XI8HST2
Pimicotinib (ABSK021), an oral, highly potent and selective small molecule blocker of the colony-stimulating factor 1 receptor (CSF-1R) independently discovered by Abbisko Therapeutics. A number of studies have shown that blocking the CSF-1R signaling pathway could effectively modulate and change macrophage functions, and potentially treat many macrophage-dependent human diseases.[1]
Pimicotinib is under investigation in clinical trial NCT05804045 (Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER)).
History
In December 2023, Abbisko Therapeutics entered into a licensing agreement for pimicotinib in all indications for China rights with Merck KGaA.[2] [3][4]
In April 2023, a global phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial designed to evaluate the safety and efficacy of pimicotinib in patients with tenosynovial giant cell tumor was started (NCT05804045).[5]
Following with pimicotinib for tenosynovial giant cell tumor treatment in phase III, pimicotinib has also entered into a phase II trial in June 2023 for cGVHD treatment in China.[6]
The U.S. Food and Drug Administration (FDA) and the Center for Drug Evaluation (CDE) of NMPA granted pimicotinib breakthrough therapy designation (BTD) for the treatment of tenosynovial giant cell tumor patients that are not amenable to surgery in January 2023 and July 2022, respectively.[7]
Research
Pimicotinib is being investigated as a treatment for tenosynovial giant cell tumor,[8][9] chronic graft-versus-host-disease (cGVHD), and pancreatic cancer.
PATENTS
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018214867&_cid=P10-MCTXKZ-70170-1
Example 41: Preparation of 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide
[0463]
[0464]Palladium carbon (50 mg) was added to a solution of 3-(benzyloxy)-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (80 mg, 0.15 mmol) in methanol (10 mL). The reaction was stirred at 50° C. for 2 hours in the presence of hydrogen. Filtered and concentrated. Plate chromatography (dichloromethane/methanol=18:1) gave 3-hydroxy-3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-carbonylpyrrolidine-1-carboxamide (10 mg, yield 15%). MS m/z(ESI):423[M+1]
[0465]
1H NMR(400MHz,DMSO-d 6)δ10.93(s,1H),8.37(d,J＝5.7Hz,1H),8.27(s,1H),8.01–7.85(m,2H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝2.4Hz,1H),6.62(dd,J＝5.7,2.4Hz,1H),5.89(s,1H),3.86(s,3H),3.83–3.76(m,1H),3.67–3.61(m,1H),2.29(s,3H),2.09–1.98(m,2H),1.34(s,3H)。
PATENTS
EP3643715
WO2018233527
US20200140431
US11180495 WO2018233527 US20200140431
References
- ^ Vaynrub A, Healey JH, Tap W, Vaynrub M (2022). “Pexidartinib in the Management of Advanced Tenosynovial Giant Cell Tumor: Focus on Patient Selection and Special Considerations”. OncoTargets and Therapy. 15: 53–66. doi:10.2147/OTT.S345878. PMC 8763255. PMID 35046667.
- ^ Merck Strengthens Oncology Portfolio Through Commercialization Agreement With Abbisko for Phase III Asset, Pimicotinib. (2023) https://www.merckgroup.com/en/news/abbisko-pimicotinib-agreement-04-12-2023.html
- ^ Merck KGaA buys into Abbisko’s late-stage joint tumor med for $70M upfront. Fierce Biotech. (2023) https://www.fiercebiotech.com/biotech/merck-kgaa-buys-abbiskos-late-stage-joint-tumor-med-70m-upfront
- ^ “Abbisko Therapeutics Announced the Entry into a Licensing Agreement for Pimicotinib (ABSK021) with Merck”. http://www.prnewswire.com (Press release). Retrieved 18 April 2024.
- ^ Study of Pimicotinib (ABSK021) for Tenosynovial Giant Cell Tumor (MANEUVER). U. S. National Institutes of Health, National Cancer Institute. https://classic.clinicaltrials.gov/ct2/show/NCT05804045
- ^ A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)U. S. National Institutes of Health, National Cancer Institute.https://classic.clinicaltrials.gov/ct2/show/NCT06186804
- ^ “FDA Grants Breakthrough Therapy Designation to Abbisko’s Pimicotinib”. Global genes. Retrieved 18 April 2024.
- ^ “Pimicotinib”. TGCT Support. Retrieved 18 April 2024.
- ^ “A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study of ABSK021 to Assess the Efficacy and Safety in Patients With Tenosynovial Giant Cell Tumor”. clinicaltrials. clinicaltrials.gov. 10 April 2024. Retrieved 18 April 2024.
External links
- “Pimicotinib”. NCI Drug Dictionary. National Cancer Institute.
- Clinical trial number NCT06186804 for “A Phase II Study Evaluating the Efficacy and Safety of ABSK021 (Pimicotinib)) in the Treatment of cGvHD Chronic Graft Versus Host Disease (cGvHD)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Other names | ABSK021 |
| Routes of administration | Oral |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2253123-16-7 |
| PubChem CID | 139549388 |
| ChemSpider | 128942304 |
| UNII | HV1XI8HST2 |
| KEGG | D12938 |
| Chemical and physical data | |
| Formula | C22H24N6O3 |
| Molar mass | 420.473 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
- [1]. Zhao BW, et al. N-(azaaryl)cyclolactam-1-carboxamide derivative, preparation method and application. World Intellectual Property Organization, WO2018214867 A1. 2018-11-29.[2]. Yang S, et al. Abstract LB-288: A highly selective small molecule CSF-1R inhibitor demonstrates strong immunomodulatory activity in syngeneic models. Cancer Research, 2018, 78(13_Supplement): LB-288-LB-288.[3]. Zhang N, et al. Abstract LB077: CSF-1R inhibition with Pimicotinib (ABSK021) enhanced anti-tumor efficacy of KRASG12C inhibitors in preclinical non-small cell lung cancer mouse models. Cancer Research, 2024, 84(7_Supplement): LB077-LB077.
//////////PIMICOTINIB, ABSK 021, Abbisko Therapeutics, HV1XI8HST2
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
join me on Linkedin
Anthony Melvin Crasto Ph.D – India | LinkedIn
join me on Researchgate
RESEARCHGATE
join me on Facebook
Anthony Melvin Crasto Dr. | Facebook
join me on twitter
Anthony Melvin Crasto Dr. | twitter
+919321316780 call whatsaapp
EMAIL. amcrasto@gmail.com
NEW DRUG APPROVALS
ONE TIME
$10.00
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
AS ON JUNE2025 4.45 LAKHS VIEWS ON BLOG WORLDREACH AVAILABLEFOR YOUR ADVERTISEMENT
join me on Linkedin
Anthony Melvin Crasto Ph.D – India | LinkedIn
join me on Researchgate
RESEARCHGATE
join me on Facebook
Anthony Melvin Crasto Dr. | Facebook
join me on twitter
Anthony Melvin Crasto Dr. | twitter
+919321316780 call whatsaapp
EMAIL. amcrasto@gmail.com
NEW DRUG APPROVALS
ONE TIME
$10.00
PALAZESTRANT
PALAZESTRANT
CAS 2092925-89-6
OP-1250, VU35KM56Q4
449.6 g/mol, C28H36FN3O
(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole
- (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-[4-(1-propylazetidin-3-yl)oxyphenyl]-1,3,4,9-tetrahydropyrido[3,4-b]indole
- (1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1-{4-[(1-propylazetidin-3- yl)oxy]phenyl}-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Palazestrant (OP-1250) is an investigational drug being developed for estrogen receptor-positive (ER+) breast cancer. It is a small molecule with a dual mechanism of action, acting as both a complete estrogen receptor antagonist and a selective estrogen receptor degrader (SERD). This means it can block estrogen receptor activity and also degrade the receptor itself, potentially offering a more effective treatment approach.
Here’s a more detailed breakdown:
- Dual Mechanism:Palazestrant is a complete ER antagonist, meaning it blocks all estrogen receptor activity. It is also a SERD, which means it degrades the estrogen receptor, preventing it from functioning.
- Oral Administration:Palazestrant is an orally available drug.
- Clinical Trials:Palazestrant is currently in clinical trials, including Phase 1/2 and Phase 3 studies, for the treatment of ER+, HER2- metastatic breast cancer.
- Combination Therapy:Palazestrant is being evaluated in combination with other drugs like CDK4/6 inhibitors (e.g., ribociclib).
- Promising Results:Preliminary results from clinical trials have shown promising antitumor efficacy and favorable pharmacokinetic properties for palazestrant.
- FDA Fast Track Designation:The FDA has granted Fast Track designation for the treatment of ER+/HER2- metastatic breast cancer that has progressed following endocrine therapy with a CDK4/6 inhibitor.
- Brain Metastasis:Palazestrant has shown activity in brain metastasis animal models.
- ESR1 Mutation Status:Palazestrant has demonstrated activity against both wild-type and mutant ER (ESR1) breast cancer models.
Palazestrant is an investigational new drug which is being evaluated for the treatment of estrogen receptor-positive (ER+) breast cancer, with a dual mechanism of action as both a complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD). This orally bioavailable small molecule has demonstrated potent activity against both wild-type and mutant forms of the estrogen receptor.[1]
SCHEME
MAIN
PAPER
https://pubs.acs.org/doi/10.1021/acsomega.4c11023
PATENTS
https://patentscope.wipo.int/search/en/detail.jsf?docId=US379744130&_cid=P22-MCPZ5L-11621-1
PATENTS’
WO2017059139
WO2023225354
WO2023091550
WO2023283329
WO2021178846
References
- ^ Parisian AD, Barratt SA, Hodges-Gallagher L, Ortega FE, Peña G, Sapugay J, et al. (March 2024). “Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination”. Molecular Cancer Therapeutics. 23 (3): 285–300. doi:10.1158/1535-7163.MCT-23-0351. PMC 10911704. PMID 38102750.
| Clinical data | |
|---|---|
| Other names | OP-1250 |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2092925-89-6 |
| PubChem CID | 135351887 |
| DrugBank | DB18971 |
| ChemSpider | 128922074 |
| UNII | VU35KM56Q4 |
| KEGG | D12827 |
| ChEMBL | ChEMBL5314475 |
| Chemical and physical data | |
| Formula | C28H36FN3O |
| Molar mass | 449.614 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
///////////PALAZESTRANT, OP 1250, A1AEA, VU35KM56Q4
Orforglipron’
Orforglipron’
CAS 2212020-52-3
C48H48F2N10O5
883.0 g/mol MW
LY-3502970
- OWL833
- 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
- 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
SCHEME
PATENT
JP2019099571
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018056453&_cid=P22-MCLODW-73083-1
<Example Compound 67>
Main cycle isomer
1 H-NMR (600 MHz, CDCl
3 ) δ: 11.32 (1H, s), 8.13 (1H, d, J
ＨＦ＝0.7 Hz), 7.59 (1H, d, J ＝8.6 Hz), 7.52 (1H, s), 7.48 (1H, dd, J ＝8.9 Hz, J
ＨＦ ＝6.9 Hz ), 7.28 (1H, d, J ＝8.9 Hz), 7.26 (1H, dd, J ＝8.6, 1.7 Hz), 7.16 (2H, d, J
ＨＦ =6.1Hz), 6.70 (1H, s), 6.61 (1H, dd, J = 3.0Hz,
JHF =1.1Hz), 6.31 (1H, d, J = 3.0Hz), 5.79 (1H, q, J = 6.7Hz), 4.4 7 (1H, dd, J=13.5, 5.2Hz), 4.12 (3H, s), 3.88 (1H, m), 3.83 (1 H, m), 3.60 (1H, ddd, J = 13.5, 12.9, 3.6Hz), 3.15 (1H, ddd, J = 15.8, 12.9, 5.2Hz), 3.04 (1H, m), 3.00 (1H, m), 2.29 (6H, d, J
HF =1.1Hz), 1.91 (1H, dd, J = 6.1, 5.8Hz), 1.79-1.76 ( 2H, m), 1.74 (1H, m), 1.65 (1H, m), 1.57 (3H, d, J=6.7 Hz), 1.60-1.55 (1H, m), 1.52 (1H, dd, J=9.5, 5.8Hz ), 1.34 (3H, s), 1.28 (3H, s), 1.20 (3H, d, J=6.0Hz).
[0437] Parainversion isomer
1 H-NMR (600 MHz, CDCl
3 ) δ: 11.27 (1H, s), 8.04 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.52 (1H, s), 7.25-7.22 (2H, m), 7.12 (1H, d, J = 8.8 Hz), 7.06 (2H, d, J
HF =6.0Hz), 6.71 (1H, s), 6.47 (1H, m), 6.08 ( 1H, d, J=3.0Hz), 5.26 (1H, q, J=6.6Hz), 4. 87 (1H, dd, J = 13.1, 4.8Hz), 4.07 (3H, s), 3 .90-3.80 (2H, m), 3.39 (1H, ddd, J = 13.1, 1 2.2, 4.6Hz), 3.08-2.97 (3H, m), 2.25 (6H, s), 1.79-1.73 (3H, m), 1.67 (3H, d, J=6.6H z), 1.64 (1H, m), 1.45-1.37 (2H, m), 1.34 ( 3H, s), 1.28 (3H, s), 1.06 (3H, d, J=6.0Hz).
Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.[1]
Orforglipron is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.[2]
Mechanism
Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.[1][3]
Clinical trials
The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.[4][5]
Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.[3]
Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo) having mild to moderate severity.[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.[1][6]
The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]
Phase III ACHIEVE-1 trial
In April 2025, results from a Phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.[1][7]
More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.[1] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[1][8]
Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[1]
References
- ^ Jump up to:a b c d e f g h “Lilly’s oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial” (Press release). Eli Lilly. April 17, 2025. Retrieved April 18, 2025.
- ^ Sidik S (2023). “Beyond Ozempic: brand-new obesity drugs will be cheaper and more effective”. Nature. 619 (7968): 19. Bibcode:2023Natur.619…19S. doi:10.1038/d41586-023-02092-9. PMID 37369789.
- ^ Jump up to:a b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). “Emerging pharmacotherapies for obesity: A systematic review”. Pharmacological Reviews. 77 (1): 100002. doi:10.1124/pharmrev.123.001045. PMID 39952695.
- ^ Pratt E, Ma X, Liu R, et al. (June 2023). “Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes”. Diabetes, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
- ^ Wharton S, Blevins T, Connery L, et al. (June 2023). “Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity”. The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
- ^ Jump up to:a b c Frias J, et al. (2023). “Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study”. The Lancet. 402 (10400): 472–83.
- ^ Constantino AK (April 17, 2025). “Eli Lilly’s weight loss pill succeeds in first late-stage trial on diabetes patients”. CNBC. Retrieved April 17, 2025.
- ^ Kolata G (April 17, 2025). “Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar”. The New York Times. ISSN 0362-4331. Retrieved April 17, 2025.
External links
- What to Know About Eli Lilly’s Daily Pill for Weight Loss, The New York Times, April 17, 2025
| Above: molecular structure of orforglipron Below: 3D representation of an orforglipron molecule | |
| Clinical data | |
|---|---|
| Other names | LY-3502970 |
| Routes of administration | Oral |
| ATC code | None |
| Pharmacokinetic data | |
| Elimination half-life | 29–49 hours |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2212020-52-3 |
| PubChem CID | 137319706 |
| ChemSpider | 71117507 |
| UNII | 7ZW40D021M |
| ChEMBL | ChEMBL4446782 |
| Chemical and physical data | |
| Formula | C48H48F2N10O5 |
| Molar mass | 882.974 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
///////////Orforglipron, LY-3502970, LY 3502970, OWL833, OWL 833
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
Olgotrelvir
Olgotrelvir
STI-1558, HY-156655, CS-0887294, STI 1558, HY 156655, CS 0887294
Cas 2763596-71-8
494.6 g/mol, C22H30N4O7S, ZP3BDH359D
C22H30N4O7S 3-Pyrrolidinepropaney, α-hydroxy-β-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, (βS,3S)-
- (2S)-2-[(S)-2-(1H-Indole-2-carboxamido)-4-methylpentanamido]-1-hydroxy-3-[(S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid
- 3-Pyrrolidinepropanesulfonic acid, alpha-hydroxy-beta-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, (betaS,3S)-
Olgotrelvir sodium, C22H30N4O7S.Na, CAS 2763596-71-8
3-Pyrrolidinepropanesulfonic acid, α-hydroxy-β-[[(2S)-2-[(1H-indol-2-ylcarbonyl)amino]-4-methyl-1-oxopentyl]amino]-2-oxo-, sodium salt (1:1), (βS,3S)-
Olgotrelvir (STI-1558) is an experimental antiviral medication being studied as a potential treatment for COVID-19. It is believed to work by inhibiting the SARS-CoV-2 main protease (Mpro), a key enzyme that SARS-CoV-2 needs to replicate,[1][2][3][4] and by blocking viral entry.[2][5]
SCHEME
Main
PATENT
US20230322668 – PROTEASE INHIBITORS AS ANTIVIRALS
Example S1: Synthesis of Compounds A-1-a, A-1-b, A-1-c and A-1-d
US20230026438 – PROTEASE INHIBITORS AS ANTIVIRALS
WO2022256434 – PROTEASE INHIBITORS AS ANTIVIRALS
Example S1: Synthesis of Compounds A-1-a, A-1-b, A-1-c and A-1-d
[00224] To a dichloromethane (2.5 L) solution of 1H-indole-2-carboxylic acid (compound 101) (200 g, 1.24 mol) and N-hydroxy succinimide (157.1 g, 1.37 mol) was added EDCI (286 g, 1.49 mmol) at 0℃. After stirring at room temperature overnight, the solvent was removed under reduced pressure. The resulting solid was triturated with deionized water, and the solid was collected and dried under reduced pressure to give the compound 102 as a light-brown solid (310 g, 96%).
1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.49 – 7.35 (m, 3H), 7.19 (t, J = 7.4 Hz, 1H), 2.92 (s, 4H).
[00225] To a stirred mixture of methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-2- oxopyrrolidin-3-yl]-propanoate (compound 103) (500 g, 1748.24 mmol) in MeOH (200 mL) was
added 4M HCl in 1,4-dioxane (2000 mL) at room temperature. The mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to afford methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride salt (compound 104) (389 g, 1721 mmol, 98%) as a light-yellow solid, which was used for next step without further purification. LCMS= [M+H]+: 187.1.
[00226] To a stirred mixture of methyl (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate hydrochloride (389 g, 1721 mmol) (compound 104) and DIEA (866.162 mL, 5240.94 mmol) in DCM (1800 mL) and EtOH (500 mL) was added 2,5-dioxopyrrolidin-1-yl (2R)-2-{[(tert-butoxy)carbonyl]amino}-4-methyl-pentanoate (compound 105) (573.66 g, 1746.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h. LCMS indicated completion of the reaction. The reaction mixture was successively washed with water (1.0 L x 2), 0.5 M HCl (1.1 L), sat. NaHCO3 (1 L) and water (1 L). The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the compound 106 (700 g, 1752.23 mmol, >99%) as a light-yellow solid, which was used for next step without further purification. LCMS = [M+H]+: 400.3.
(400 MHz, DMSO-d6) δ 8.32 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.40 – 4.28 (m, 1H), 3.94 (dd, J = 15.1, 8.1 Hz, 1H), 3.74 – 3.52 (m, 3H), 3.15 (t, J = 8.8 Hz, 1H), 3.06 (dd, J = 16.4, 9.2 Hz, 1H), 2.33 (t, J = 9.2 Hz, 1H), 2.14 – 2.00 (m, 2H), 1.68 – 1.51 (m, 3H), 1.42 – 1.34 (m, 11H), 0.87 (dd, J = 11.4, 6.6 Hz, 6H).
[00227] A mixture of methyl (2S)-2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanamido]-3-[(3S)-2-oxopyrrolidin-3-yl]propanoate (compound 106) (590 g, 1476.88 mmol) in HCl/dioxane (3 L) was stirred at room temperature for 2 h. LC-MS indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure to give compound 107 as a yellow solid (490 g, 99%), which was used for next step without further purification.
LCMS = [M+H]+: 300.2.
[00228] To a stirred mixture of methyl (S)-2-((S)-2-amino-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate hydrochloride (compound 107) (418 g, 1235 mmol) and TEA (519.020 mL, 3734.03 mmol) in DMF (2500 mL) at room temperature was added 2,5-dioxopyrrolidin-1-yl 1H-indole-2-carboxylate (compound 102) (353 g, 1369.15 mmol) . The reaction mixture was stirred for 1.5 h. LCMS indicated that the reaction was complete. EtOAc (6 L) was added into the reaction mixture, which was then washed with brine (6 L x 6). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated down under reduced
pressure. Compound A-1-a was obtained as an off-white solid (414 g. Y: 76%), which was used for next step without further purification. LCMS = [M+H]+: 443.3. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 8.54 (t, J = 12.2 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.24 (t, J = 10.3 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 4.65 – 4.50 (m, 1H), 4.44 – 4.28 (m, 1H), 3.72 – 3.55 (s, 3H), 3.19 – 3.06 (m, 2H), 2.36 (ddd, J = 13.8, 10.3, 4.0 Hz, 1H), 2.16 – 2.03 (m, 2H), 1.79 – 1.49 (m, 5H), 0.92 (dt, J = 14.4, 7.2 Hz, 6H).
[00229] To a stirred solution of methyl (S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (compound A-1-a) (500 g, 1131 mmol) in THF (20 L) LiBH4 (74 g, 3393 mmol) was added portionwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 4 h. After reaction was completed (monitored by LCMS), the reaction mixture was quenched with sat. aqueous NH4Cl until no more gas formed. The mixture was washed with brine (5 L x 4), organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated down in vacuum. The resulting residue was purified by silica column chromatography (DCM : MeOH = 15 : 1) to give the desired product compound A-1-b (310 g, 66%) as a white solid. LCMS = [M+H]+: 415.2.
NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.50 (td, J = 9.7, 5.0 Hz, 1H), 3.80 (s, 1H), 3.40 – 3.28 (m, 1H), 3.28 – 3.20 (m, 1H), 3.15 – 2.99 (m, 2H), 2.33 – 2.20 (m, 1H), 2.12 (dt, J = 17.8, 9.4 Hz, 1H), 1.86 – 1.75 (m, 1H), 1.75 – 1.64 (m, 2H), 1.56 (ddd, J = 19.3, 9.6, 6.9 Hz, 2H), 1.45 – 1.35 (m, 1H), 0.91 (dd, J = 15.6, 6.3 Hz, 6H).
[00230] To a stirred solution of N-((S)-1-(((S)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-4-methyl-1-oxopentan-2-yl)-1H-indole-2-carboxamide (compound A-1-b) (8.3 g, 20 mmol) in DMSO (60 mL) was added 2-iodoxybenzoic acid (IBX) (11.2 g, 40 mmol) at room temperature. The reaction mixture was stirred at 30 ℃ for 18 h, and LCMS indicated completion of the reaction. The reaction mixture was diluted with EtOAc (300 mL) and filtered. The filtrate was washed with mixture of brine and sat. aqueous NaHCO3 (1:1 to 5:1, 200 mL x 5). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated down at rt to afford crude product. THF (40 mL) was added, and the mixture was stirred overnight at room temperature. The resulting solid was collected and dried under vacuum to yield the desired product N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)-propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) as a white solid (2.5 g, 31%). LCMS = [M+H]+:
413.2. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.64 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.14-7.05 (m, 2H), 7.01 (s, 1H), 6.34 (s, 1H), 4.90 (s, 1H), 4.34 (s, 1H), 3.27–3.22 (m, 2H), 2.43 (s, 1H), 2.30 (s, 1H), 2.01-1.96 (m, 1H), 1.94-1.91 (m, 1H) 1.88 – 1.65 (m, 4H), 1.00-0.98 (m, 6H).
[00231] To a stirred solution of N-((S)-4-methyl-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)pentan-2-yl)-1H-indole-2-carboxamide (compound A-1-c) (31 g, 75.25 mmol) in EtOAc (300 mL) at room temperature was added a solution of NaHSO3 (27.56 mg, 72.73 mmol) in water (100 mL). The reaction mixture was heated at 50 ℃ for 3 h. After completion of reaction (monitored by LCMS), the organic layer was separated and removed. The aqueous layer was washed with EtOAc (100 mL x 5), concentrated down to remove remaining EtOAc, and then lyophilized to provide the desired product sodium (2S)-2-((S)-2-(1H-indole-2-carboxamido)-4-methylpentanamido)-1-hydroxy-3-((S)-2-oxopyrrolidin-3-yl)propane-1-sulfonate (compound A-1-d) as off-white solid (32 g, 85%). LCMS = [M-Na+2H]+: 495.2. 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.45 (dd, J = 20.7, 8.2 Hz, 1H), 7.72 (dd, J = 48.9, 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.25 (dd, J = 5.1, 1.4 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 5.43 (dd, J = 50.7, 5.9 Hz, 1H), 4.57 – 4.41 (m, 1H), 4.33 – 4.03 (m, 1H), 4.01 – 3.82 (m, 1H), 3.19 – 2.92 (m, 2H), 2.29 – 2.08 (m, 2H), 2.06 – 1.90 (m, 1H), 1.83 – 1.51 (m, 5H), 1.00 – 0.83 (m, 6H).
PAPER
https://www.sciencedirect.com/science/article/pii/S2666634023004026
Mechanism of action
Olgotrelvir is a prodrug that first converts to its active form, AC1115.[2][5] AC1115 is believed to work by inhibiting the SARS-CoV-2 main protease (also known as 3C-like protease). This protein is a crucial enzyme responsible for cleaving viral polyproteins into functional subunits essential for viral replication. By binding to the active site of the protease, the drug prevents this cleavage process, effectively halting viral assembly and impeding the virus’s ability to produce future virions.[1][2][3][5]
Olgotrelvir also appears to inhibit cathepsin L (CTSL),[2][5] a protein implicated in facilitating viral entry of SARS-CoV-2 into the host cell.[2][5][6]
Clinical trials
In September 2023, the drug’s developer, Sorrento Therapeutics, announced top-line data that olgotrelvir had met its primary endpoints in a phase III clinical trial that enrolled 1,212 patients with mild or moderate COVID-19. The drug appeared to shorten the recovery time of 11 COVID-19 symptoms in olgotrelvir-treated patients by 2.4 days on average compared to patients in the placebo group. The drug was also shown to reduce the viral load at day 4 in treated patients compared to the placebo group. Side effects were mostly mild and infrequent, with the most common being nausea (1.5% vs. 0.2%) and skin rash (3.3% vs. 0.3%), which occurred more often in the olgotrelvir group.[7][8][9]
References
- ^ Jump up to:a b Tong X, Keung W, Arnold LD, Stevens LJ, Pruijssers AJ, Kook S, et al. (November 2023). “Evaluation of in vitro antiviral activity of SARS-CoV-2 Mpro inhibitor pomotrelvir and cross-resistance to nirmatrelvir resistance substitutions”. Antimicrobial Agents and Chemotherapy. 67 (11): e0084023. doi:10.1128/aac.00840-23. PMC 10649086. PMID 37800975.
Other examples of Mpro inhibitors in late-stage development include STI-1558, currently in the phase 3 clinical trial in adult subjects with mild or moderate COVID-19 (NCT05716425).
- ^ Jump up to:a b c d e f Hackett DW (26 June 2023). “Second Generation Oral Mpro Inhibitor for COVID-19 Treatment Proceeds in Phase 3 Study”. Precision Vaccinations. Retrieved 27 December 2023.
- ^ Jump up to:a b “Coronavirus disease 2019 (COVID-19) emerging treatments”. BMJ Best Practice US. Archived from the original on 27 December 2023. Retrieved 27 December 2023.
- ^ Janin YL (September 2023). “On the origins of SARS-CoV-2 main protease inhibitors”. RSC Medicinal Chemistry. 15 (1): 81–118. doi:10.1039/D3MD00493G. ISSN 2632-8682. PMC 10809347. PMID 38283212. S2CID 264103864.
- ^ Jump up to:a b c d e Mao L, Shaabani N, Zhang X, Jin C, Xu W, Argent C, et al. (January 2024). “Olgotrelvir, a dual inhibitor of SARS-CoV-2 Mpro and cathepsin L, as a standalone antiviral oral intervention candidate for COVID-19”. Med (New York, N.Y.). 5 (1): 42–61.e23. doi:10.1016/j.medj.2023.12.004. PMID 38181791.
- ^ Berdowska I, Matusiewicz M (October 2021). “Cathepsin L, transmembrane peptidase/serine subfamily member 2/4, and other host proteases in COVID-19 pathogenesis – with impact on gastrointestinal tract”. World Journal of Gastroenterology. 27 (39): 6590–6600. doi:10.3748/wjg.v27.i39.6590. PMC 8554394. PMID 34754154.
- ^ Jiang R, Han B, Xu W, Zhang X, Peng C, Dang Q, et al. (June 2024). “Olgotrelvir as a Single-Agent Treatment of Nonhospitalized Patients with Covid-19”. NEJM Evidence. 3 (6): EVIDoa2400026. doi:10.1056/EVIDoa2400026. PMID 38804790.
- ^ Sherman AC, Baden LR (June 2024). “How To Measure Benefit in a Changing Pandemic – Olgotrelvir for SARS-CoV-2”. NEJM Evidence. 3 (6): EVIDe2400144. doi:10.1056/EVIDe2400144. PMID 38804789.
- ^ “Sorrento Announces Phase 3 Trial Met Primary Endpoint and Key Secondary Endpoint in Mild or Moderate COVID-19 Adult Patients Treated with Ovydso (Olgotrelvir), an Oral Mpro Inhibitor as a Standalone Treatment for COVID-19” (Press release). BioSpace. 12 September 2023. Retrieved 27 December 2023.
| Clinical data | |
|---|---|
| Trade names | Ovydso |
| Other names | STI-1558, HY-156655, CS-0887294 |
| Routes of administration | By mouth |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 2763596-71-8 |
| PubChem CID | 166157331 |
| UNII | ZP3BDH359D |
| KEGG | D12777 |
| Chemical and physical data | |
| Formula | C22H30N4O7S |
| Molar mass | 494.56 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
//////Olgotrelvir, STI-1558, HY-156655, CS-0887294, STI 1558, HY 156655, CS 0887294, ZP3BDH359D
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
