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VODOBATINIB
VODOBATINIB
1388803-90-4
| Molecular Weight | 453.92 |
|---|---|
| Appearance | Solid |
| Formula | C27H20ClN3O2 |
- SCO-088
- K0706
- K-0706
2-chloro-6-methyl-N‘-[4-methyl-3-(2-quinolin-3-ylethynyl)benzoyl]benzohydrazide
Vodobatinib (K0706) is a potent, third generation and orally active Bcr-Abl1 tyrosine kinase inhibitor with an IC50 of 7 nM. Vodobatinib exhibits activity against most BCR-ABL1 point mutants, and has no activity against BCR-ABL1T315I. Vodobatinib can be used for chronic myeloid leukemia (CML) research. Vodobatinib is a click chemistry reagent, itcontains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups.
| Vodobatinib (K0706) is a potent, third generation and orally active Bcr-Abl1 tyrosine kinase inhibitor with an IC50 of 7 nM. Vodobatinib exhibits activity against most BCR-ABL1 point mutants, and has no activity against BCR-ABL1T315I. Vodobatinib can be used for chronic myeloid leukemia (CML) research[1][2]. Vodobatinib is a click chemistry reagent, itcontains an Alkyne group and can undergo copper-catalyzed azide-alkyne cycloaddition (CuAAc) with molecules containing Azide groups. |
Brain penetrant kinase inhibitors: Learning from kinase neuroscience discovery
Publication Name: Bioorganic & Medicinal Chemistry Letters
Publication Date: 2018-06-15
PMID: 29752185
DOI: 10.1016/j.bmcl.2018.05.007
PATENT
WO2012098416
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012098416
EXAMPLES
Reƒerence Example 1
Methyl 3-ethynyl-4-methylbenzoate
A mixture of methyl 3-iodo-4-methylbenzoate (2.0g, 7mmol), trimethylsilylacetylene (1.2ml, 8mmol), Pd(PPh3)4 (0.42g, 0.3mmol), CuI (0.137g, 0.7mmol) and diisopropylethylamine (2.5ml, 11.4mmol) in THF (20ml) was heated at 50°C for 12hrs under nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and filtered through a Celite® bed. The clear filtrate was concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate.
To the solution of methyl 4-methyl-3-[(trimethylsilyl)ethynyl]benzoate (2.3g) in THF (40ml) was added tetrabutylammonium fluoride (1.0M in THF, 3.2ml, 1 1mmol) at ambient
temperature and stirred for 15 minutes, concentrated and the residue purified by flash chromatography on silica gel (elution with 2% ethyl acetate in n-hexane) to provide methyl 3 – ethynyl- 4-methylbenzo at e .
1H NMR (500 MHz in DMSO-d6), δ 2.50 (s, 3H), 3.90 (s, 3H), 4.57 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.99 (s, 1H).
Similarly were prepared the following ester compounds from their corresponding iodo esters:
Methyl 3-ethynyl-4-fluorobenzoate
Methyl 3-ethynyl-4-methoxybenzoate
Reƒerence Example 2
4-Methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid
A mixture of methyl 3-ethynyl-4-methylbenzoate (0.341 g, 2mmol), 3-iodoquinoline (0.5g, 2mmol), Pd(PPh3)4 (0.1 1g, 0.01mmol), CuI (0.179g, 0.1mmol) and diisopropylethylamine (0.5ml, 3mmol) in DMF (15ml) was stirred at ambient temperature for 12hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoate.
Sodium hydroxide (0.15g, 3.71mmol) was added to a solution of the above methyl ester in methanol (20ml) and water (3ml) and stirred at 50°C for 3hrs and then concentrated in vacuo. Water (10ml) was added to the residue, adjusted pH to 4.0-4.5 with citric acid. The solid obtained was filtered, washed successively with water and diethyl ether and dried at ambient temperature to obtain 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid. 1H NMR (500 MHz in DMSO-d6), δ 2.66 (s, 3H), 7.56 (d, J = 8.0 Hz, 1H), 7.75 (t, J; = 15.1 Hz, J2 = 8.2 Hz, 1H), 7.89 (t, J} = 13.7 Hz, J2 = 8.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 8.17 (s, 1H), 8.75 (s, 1H), 9.1 1 (s, 1H), 12.84 (s, 1H).
Reƒerence Example 3
4-Methyl-3-[2-(3-quinolyl)ethynyl]benzohydrazide
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid (0.15g, 0.5mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (0.15g, 0.7mmol) and 1-hydroxybenzotriazole (0.1g, 0.7mmol) in N,N-dimethylformamide (15ml) was stirred at room temperature for 1hr. Hydrazine hydrate (1.52ml, 0.5mmol) was then added and the mixture stirred for another 3hrs. Concentration and trituration of the residue with water produced a solid which was filtered, washed successively with water and diethyl ether, and finally dried in vacuo to get the hydrazide as a pale yellow solid.
1H NMR (400 MHz in DMSO-d6), δ 2.63 (s, 3H), 4.79 (s, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.75 (t, J1 = 14.7 Hz, J2 = 7.6 Hz, 1H), 7.85-7.96 (m, 2H), 8.09-8.13 (m, 3H), 8.73 (s, 1H), 9.09 (s, 1H), 9.91 (s, 1H).
Reƒerence Example 4
N’-(3-iodo-4-methylbenzoyl)-2,4,6-trichlorobenzohydrazide
N’-(3-iodo-4-methylbenzoyl)-2,4,6-trichlorobenzohydrazide was prepared by the reaction of 3-iodo-4-methylbenzoic acid with 2,4,6-trichlorobenzohydrazide. The coupling was performed in a manner similar to that described in Reference Example 3.
Example 1.1
2,4,6-Trichloro-N’-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl]benzohydrazide
Method A:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid (0.15g, 0.5mmol), N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (0.15g, 0.7mmol) and 1-hydroxybenzotriazole (0.1g, 0.7mmol) in N,N-dimethylformamide (15ml) was stirred at ambient temperature for 1hr. 2,4,6-Trichlorobenzohydrazide (0.125g, 0.5mmol) was added and the mixture stirred for 12hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and the crude product was purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to get 2,4,6-trichloro-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl] benzohydrazide as a white solid.
Method B:
2,4,6-Trichloro-N’-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl] benzohydrazide was also prepared by the reaction of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid with 2,4,6-trichlorobenzohydrazide in diethyl cyanophosphonate. The condensation reaction was performed in a manner similar to that described in Method A.
Method C:
2,4,6-Trichloro-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl]benzohydrazide was also prepared by the reaction of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzohydrazide with 2,4,6- trichlorobenzoyl chloride. The condensation reaction was performed in a manner similar to that described in Method A.
The compounds 1.2 to 1.14, 1.21 to 1.34, 1.36 to 1.40, and 1.43 to 1.59 were prepared in a manner similar to Example I.1, by following either of the methods A, B or C, using the appropriate substrates.
PATENT
WO2023214314 VODOBATINIB FOR REDUCING PROGRESSION OF PARKINSON’S DISEASE (wipo.int)
Vodobatinib (N’-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl) ethynyl]-benzohydrazide), a c-Abl inhibitor is represented by Formula I (referred hereinafter interchangeably as vodobatinib or compound of Formula
International Publication Nos. WO 2017/208267A1, WO 2020/250133 Al and WO 2022/024072A1, which are hereby incorporated by reference, disclose methods of use of the compound of Formula I for the treatment of Parkinson’s disease, synucleinopathies and Alzheimer’s disease (AD) respectively.
There is a continuing need for effective and safe methods for the treatment of, and delaying the progression of, neurodegenerative diseases, including in the early-stage of the diseases.
- N’-(2-chloro-6-methylbenzoyl)-4-methyl-3-[2-(3-quinolyl) ethynyl]-benzohydrazide for treatment of alzheimer’s diseasePublication Number: WO-2022024072-A1Priority Date: 2020-07-31
- Compounds for the treatment of covid-19Publication Number: EP-3875078-A1Priority Date: 2020-03-06
- Treatment for synucleinopathiesPublication Number: US-2022257582-A1Priority Date: 2019-06-11
- Novel amorphous dispersion of 4-Methyl-3-quinolin-3-ylethynyl-benzoic acid N’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: AU-2018235446-A1Priority Date: 2017-03-15
- Novel amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: EP-3596050-A1Priority Date: 2017-03-15
- Novel amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: US-2020085751-A1Priority Date: 2017-03-15
- Novel amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: WO-2018167802-A1Priority Date: 2017-03-15
- NOVEL AMORPHOUS DISPERSION OF 4-METHYL-3-QUINOLIN-3-YETHYNYL-BENZOIC ACID HYDRAZIDE N- (2-CHLORO-6-METHYL-BENZOYL)Publication Number: WO-2018167802-A9Priority Date: 2017-03-15
- Novel amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: US-2021267906-A1Priority Date: 2017-03-15
- Novel amorphous dispersion of 4-Methyl-3-quinolin-3-ylethynyl-benzoic acid N’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: AU-2018235446-B2Priority Date: 2017-03-15Grant Date: 2022-04-07
- Amorphous dispersion of 4-methyl-3-quinolin-3-ylethynyl-benzoic acid n’-(2-chloro-6-methyl-benzoyl) hydrazidePublication Number: US-11351123-B2Priority Date: 2017-03-15Grant Date: 2022-06-07
- Treatment of parkinson’s diseasePublication Number: US-2019275017-A1Priority Date: 2016-06-02
- Treatment of Parkinson’s diseasePublication Number: US-10849887-B2Priority Date: 2016-06-02Grant Date: 2020-12-01
- Treatment of Parkinson’s diseasePublication Number: IL-263188-APriority Date: 2016-06-02
- Treatment of Parkinson’s diseasePublication Number: CN-109475539-BPriority Date: 2016-06-02Grant Date: 2021-12-28
- Treatment of Parkinson’s diseasePublication Number: JP-6974357-B2Priority Date: 2016-06-02Grant Date: 2021-12-01
- Treatment for parkinson’s diseasePublication Number: US-2022273632-A1Priority Date: 2016-06-02
- Diarylacetylene hydrazide containing tyrosine kinase inhibitorsPublication Number: AU-2012208388-A1Priority Date: 2011-01-21
- Diarylacetylene hydrazide containing tyrosine kinase inhibitorsPublication Number: AU-2012208388-A2Priority Date: 2011-01-21
- Diarylacetylene hydrazide containing tyrosine kinase inhibitorsPublication Number: EP-2665709-B1Priority Date: 2011-01-21Grant Date: 2016-12-07
- Tyrosine kinase inhibitors containing diarylacetylene hydrazidePublication Number: ES-2608829-T3Priority Date: 2011-01-21Grant Date: 2017-04-17
- Diarylacetylene hydrazide containing tyrosine kinase inhibitorsPublication Number: US-2013296557-A1Priority Date: 2011-01-21
- Diarylacetylene hydrazide containing tyrosine kinase inhibitorsPublication Number: US-9024021-B2Priority Date: 2011-01-21Grant Date: 2015-05-05
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Ref
- [1]. Orlando Antelope, et al. BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia. Exp Hematol. 2019 Sep;77:36-40.e2. [Content Brief][2]. Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib. Session: 632: Chronic Myeloid Leukemia: Therapy: CML: New and Beyond.
///////VODOBATINIB, SCO-088, K0706, K-0706
CC1=C(C(=CC=C1)Cl)C(=O)NNC(=O)C2=CC(=C(C=C2)C)C#CC3=CC4=CC=CC=C4N=C3
Zuranolone
Zuranolone
CAS 1632051-40-1
FDA APPROVED 8/4/2023, To treat postpartum depression
Press Release
WeightAverage: 409.574
Monoisotopic: 409.272927379Chemical FormulaC25H35N3O2
- SAGE 217
- SAGE-217
- SAGE217
Zuranolone, sold under the brand name Zurzuvae, is a medication used for the treatment of postpartum depression.[1][2] It is taken by mouth.[1]
The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis, and urinary tract infection.[1][2] An orally active inhibitory pregnane neurosteroid, zuranolone acts as a positive allosteric modulator of the GABAA receptor.[6][7][8]
Zuranolone was approved for medical use in the United States for the treatment of postpartum depression in August 2023.[2] It was developed by Sage Therapeutics and Biogen.[9]
Medical uses
Zuranolone is indicated for the treatment of postpartum depression.[1][2]
Adverse effects
The most common side effects include drowsiness, dizziness, diarrhea, fatigue, nasopharyngitis (cold-like symptoms), and urinary tract infection.[2]
The US FDA label contains a boxed warning noting that zuranolone can impact a person’s ability to drive and perform other potentially hazardous activities.[2] Use of zuranolone may cause suicidal thoughts and behavior.[2] Zuranolone may cause fetal harm.[2]
History
Zuranolone was developed as an improvement on the intravenously administered neurosteroid brexanolone, with high oral bioavailability and a biological half-life suitable for once-daily administration.[7][10] Its half-life is around 16 to 23 hours, compared to approximately 9 hours for brexanolone.[4][5]
The efficacy of zuranolone for the treatment of postpartum depression in adults was demonstrated in two randomized, double-blind, placebo-controlled, multicenter studies.[2] The trial participants were women with postpartum depression who met the Diagnostic and Statistical Manual of Mental Disorders criteria for a major depressive episode and whose symptoms began in the third trimester or within four weeks of delivery.[2] In study 1, participants received 50 mg of zuranolone or placebo once daily in the evening for 14 days.[2] In study 2, participants received another zuranolone product that was approximately equal to 40 mg of zuranolone or placebo, also for 14 days.[2] Participants in both studies were monitored for at least four weeks after the 14-day treatment.[2] The primary endpoint of both studies was the change in depressive symptoms using the total score from the 17-item Hamilton depression rating scale (HAMD-17), measured at day 15.[2] Participants in the zuranolone groups showed significantly more improvement in their symptoms compared to those in the placebo groups.[2] The treatment effect was maintained at day 42—four weeks after the last dose of zuranolone.[2]
Society and culture
Zuranolone is the international nonproprietary name.[11]
Legal status
Zuranolone was approved by the US Food and Drug Administration (FDA) for the treatment of postpartum depression in August 2023.[2][12] The FDA granted the application for zuranolone priority review and fast track designations.[2] Approval of Zurzuvae was granted to Sage Therapeutics, Inc.[2]
Zuranolone has also been under development for the treatment of major depressive disorder, but the application for this use was given a Complete Response Letter (CRL) by the FDA due to insufficient evidence of effectiveness.[13]
Research
In a randomized, placebo-controlled phase III trial to assess its efficacy and safety for the treatment of major depressive disorder, subjects in the zuranolone group (50 mg oral zuranolone once daily for 14 days) experienced statistically significant and sustained improvements in depressive symptoms (as measured by HAM-D score) throughout the treatment and follow-up periods of the study.[14]
Other investigational applications include insomnia, bipolar depression, essential tremor, and Parkinson’s disease.[15][6][16]
syn
PATENT
WO2022020363
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022020363&_cid=P11-LLRZ9A-38538-1
Example 1. Synthesis of 1-(2-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (Compound 1).
[00488] To a suspension of K2CO3 (50 mg, 0.36 mmol) in THF (5 mL) was added 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol) and 2-bromo-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[ ^]phenanthren-17-yl)ethan-1-one (50 mg, 0.12 mmol). The mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into 5 mL H2O and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified by reverse-phase preparative HPLC to afford Compound 1 as a white solid (9 mg, 17.4% yield).1H NMR (500 MHZ, CDCl3) δ (ppm) 7.87 (1H, s), 7.82 (1H, s), 5.02 (1H, AB), 4.2 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dxt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt=2.24 min, m/z=410.1 [M+H]+.
PAPER
Journal of Medicinal Chemistry (2017), 60(18), 7810-7819
https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00846
Certain classes of neuroactive steroids (NASs) are positive allosteric modulators (PAM) of synaptic and extrasynaptic GABAA receptors. Herein, we report new SAR insights in a series of 5β-nor-19-pregnan-20-one analogues bearing substituted pyrazoles and triazoles at C-21, culminating in the discovery of 3α-hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217, 3), a potent GABAA receptor modulator at both synaptic and extrasynaptic receptor subtypes, with excellent oral DMPK properties. Compound 3 has completed a phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) clinical trial and is currently being studied in parallel phase 2 clinical trials for the treatment of postpartum depression (PPD), major depressive disorder (MDD), and essential tremor (ET).
3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19- nor-5β-pregnan-20-one (3). Yield: 28 g (49%) as an off-white solid. LC-MS: tR = 1.00 min, m/z = 410 (M + 1). 1 H NMR (400 MHz, CDCl3): δ 7.86 (s, 1H), 7.80 (s, 1H), 5.08−4.84 (m, 2H), 2.70−2.55 (m, 1H), 2.25−2.15 (m, 1H), 2.10−2.00 (m, 1H), 1.88−1.59 (m, 7H), 1.53−1.30 (m, 15H), 1.25−1.00 (m, 3H), 0.67 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 13.92 (CH3), 23.20, 24.44, 25.54, 25.78, 26.15 (5 × CH2), 26.69 (CH3), 31.43, 34.61 (2 × CH2), 34.77, 37.71 (2 × CH), 39.26 (CH2), 40.35 (CH), 41.21 (CH2), 41.75 (CH), 45.56 (C), 56.04, 61.24 (2 × CH), 61.78 (CH2), 72.14 (C), 93.25 (C), 113.35 (CN), 136.16, 142.49 (2 × CH), 202.23 (CO). HRMS m/z 410.2803 calcd for C25H36N3O2 + 410.2802
PATENT
WO2014169833
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014169833&_cid=P11-LLRZJ9-40598-1
Synthetic Procedures
The compounds of the invention can be prepared in accordance with methods described in the art (Upasmi et al., J. Med. Chem. 1997, 40:73-84; and Hogenkamp et al., J. Med. Chem. 1997, 40:61- 72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. In some embodiments, compounds described herein can be prepared using methods shown in general Schemes 1-4, comprising a nucleophilic substitution of 19-nor pregnane bromide with a neucleophile. In certain embodiments, the nucleophile reacts with the 19-nor pregnane bromide in the presence of K2CO3 in THF.
Synthesis of compound SA-B. Compound SA (50 g, 184 mmol) and palladium black (2.5 g) in tetrahydrofuran (300 mL) and concentrated hydrobromic acid (1.0 mL) was hydrogenated with 10 atm hydrogen. After stirring at room temperature for 24h, the mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude compound. Recrystallization from acetone gave compound SA-B (42.0 g, yield: 83.4%) as white powder.
1H NMR: (400 MHz, CDCl3) δ 2.45-2.41 (m, 1H), 2.11-3.44 (m, 2H), 3.24 (s, 3H), 2.18-2.15 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.57 (m, 7H), 1.53-1.37 (m, 7H), 1.29-1.13 (m, 3H), 1.13-0.90 (m, 2H), 0.89 (s, 3H).
Synthesis of compound SA-C. A solution of SA-B (42.0 g, 153.06 mmol) in 600 mL anhydrous toluene was added dropwise to the methyl aluminum bis(2,6-di-tert-butyl-4-methylphenoxide (MAD) (459.19 mmol, 3.0 eq, freshly prepared) solution under N2 at -78°C. After the addition was completed, the reaction mixture was stirred for 1 hr at -78°C. Then 3.0 M MeMgBr (153.06 mL, 459.19 mmol) was slowly added dropwise to the above mixture under N2 at -78°C. Then the reaction mixture was stirred for 3 hr at this temperature. TLC (Petroleum ether/ethyl acetate = 3:1) showed the reaction was completed. Then saturated aqueous NH4Cl was slowly added dropwise
to the above mixture at -78°C. After the addition was completed, the mixture was filtered, the filter cake was washed with EtOAc, the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated, purified by flash Chromatography on silica gel (Petroleum ether/ ethyl acetate20:1 to 3:1) to afford compound SA-C (40.2 g, yield: 90.4%) as white powder. 1H NMR: (400 MHz, CDCl3) δ 2.47-2.41 (m, 1H), 2.13-2.03 (m, 1H), 1.96-1.74 (m, 6H), 1.70-1.62 (m, 1H), 1.54-1.47 (m, 3H), 1.45-1.37 (m, 4H), 1.35-1.23 (m, 8H), 1.22-1.10 (m, 2H), 1.10-1.01 (m, 1H), 0.87 (s, 3H).
Synthesis of compound SA-D. To a solution of PPh3EtBr (204.52 g, 550.89 mmol) in THF (500 mL) was added a solution of t-BuOK (61.82 g, 550.89 mmol) in THF (300 mL) at 0°C. After the addition was completed, the reaction mixture was stirred for 1 h 60 °C, then SA-C (40.0 g, 137.72 mmol) dissolved in THF (300 mL) was added dropwise at 60°C. The reaction mixture was heated to 60 °C for 18 h. The reaction mixture was cooled to room temperature and quenched with Sat. NH4Cl, extracted with EtOAc (3*500 mL). The combined organic layers were washed with brine, dried and concentrated to give the crude product, which was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 10:1) to afford compound SA-D (38.4 g, yield:92%) as a white powder. 1H NMR: (400 MHz, CDCl3) δ 5.17-5.06 (m, 1H), 2.42-2.30 (m, 1H), 2.27-2.13 (m, 2H), 1.89-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.55-1.43 (m, 4H), 1.42-1.34 (m, 3H), 1.33-1.26 (m, 6H), 1.22-1.05 (m, 5H), 0.87 (s, 3H).
Synthesis of compound SA-E. To a solution of SA-D (38.0 g, 125.62 mmol) in dry THF (800 mL) was added dropwise a solution of BH3.Me2S (126 mL, 1.26 mol) under ice-bath. After the addition was completed, the reaction mixture was stirred for 3 h at room temperature (14-20 °C). TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed. The mixture was cooled to 0 °C and 3.0 M aqueous NaOH solution (400 mL) followed by 30% aqueous H2O2 (30%, 300 mL) was added. The mixture was stirred for 2 h at room temperature (14-20 °C), and then filtered, extracted with EtOAc (3*500 mL). The combined organic layers were washed with saturated aqueous Na2S2O3, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product (43 g , crude) as colorless oil. The crude product was used in the next step without further purification.
Synthesis of compound SA-F. To a solution of SA-E (43.0 g, 134.16 mmol) in dichloromethane (800 mL) at 0 °C and PCC (53.8 g, 268.32 mmol) was added portion wise. Then the reaction mixture was stirred at room temperature (16-22 °C) for 3 h. TLC (Petroleum ether/ ethyl acetate3:1) showed the reaction was completed, then the reaction mixture was filtered, washed with DCM. The organic phase was washed with saturated aqueous Na2S2O3, brine, dried over Na2SO4 and concentrated in vacuum to give the crude product. The crude product was purified by a flash column chromatography (Petroleum ether/ ethyl acetate50:1 to 8:1) to afford compound SA-F (25.0 g, yield:62.5%, over two steps) as a white powder. 1H NMR (SA-F): (400 MHz, CDCl3) δ 2.57-2.50 (m, 1H), 2.19-2.11 (m, 4H), 2.03-1.97 (m, 1H), 1.89-1.80 (m, 3H), 1.76-1.58 (m, 5H), 1.47-1.42 (m, 3H), 1.35-1.19 (m, 10H), 1.13-1.04 (m, 3H), 0.88-0.84 (m, 1H), 0.61 (s, 3H).
Synthesis of compound SA. To a solution of SA-F (10 g, 31.4 mmol) and aq. HBr (5 drops, 48% in water) in 200 mL of MeOH was added dropwise bromine (5.52 g, 34.54 mmol). The reaction mixture was stirred at 17 °C for 1.5 h. The resulting solution was quenched with saturated aqueous NaHCO3 at 0°C and extracted with EtOAc (150 mLx2). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel eluted with (PE: EA=15:1 to 6:1) to afford compound SA (9.5 g, yield: 76.14%) as a white solid. LC/MS: rt 5.4 mm ; m/z 379.0, 381.1, 396.1.
To a suspension of K2CO3 (50 mg, 0.36mmol) in THF (5 mL) was added ethyl 1H-pyrazole-4-carbonitrile (100 mg, 0.97 mmol ) and SA (50 mg,0.12 mmol). The mixture was stirred at rt for 15h. The reaction mixture was poured in to 5 mL H2O and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue mixture was purified with by reverse-phase prep-HPLC to afford the title compound as a white solid (9mg, 17.4%). 1H NMR (500 MHz, CDCl3), δ (ppm) 7.87 (1H, s),
7.82 (1H, s), 5.02 (1H, AB), 4.92 (1H, AB), 2.61 (1H, t), 2.16-2.24 (1H, m), 2.05 (1H, dXt), 1.70-1.88 (6H, m), 1.61-1.69 (2H, m), 1.38-1.52 (6H, m), 1.23-1.38 (5H, m), 1.28 (3H, s), 1.06-1.17 (3H, m), 0.67 (3H, s). LCMS: rt = 2.24 mm, m/z = 410.1 [M+H]+.
PATENT
WO2020150210
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References
- ^ Jump up to:a b c d e “Zurzuvae (zuranolone) capsules, for oral use, [controlled substance schedule pending]” (PDF). Archived (PDF) from the original on 5 August 2023. Retrieved 5 August 2023.
- ^ Jump up to:a b c d e f g h i j k l m n o p q r s t “FDA Approves First Oral Treatment for Postpartum Depression”. U.S. Food and Drug Administration (FDA) (Press release). 4 August 2023. Retrieved 4 August 2023.
This article incorporates text from this source, which is in the public domain. - ^ Jump up to:a b “Zuranolone”. DrugBank Online.
- ^ Jump up to:a b Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, et al. (2022). “GABAkines – Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors”. Pharmacology & Therapeutics. 234: 108035. doi:10.1016/j.pharmthera.2021.108035. PMC 9787737. PMID 34793859. S2CID 244280839.
- ^ Jump up to:a b Faden J, Citrome L (2020). “Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used?”. Therapeutic Advances in Psychopharmacology. 10: 2045125320968658. doi:10.1177/2045125320968658. PMC 7656877. PMID 33224470.
- ^ Jump up to:a b “SAGE 217”. AdisInsight. Archived from the original on 29 March 2019. Retrieved 10 February 2018.
- ^ Jump up to:a b Blanco MJ, La D, Coughlin Q, Newman CA, Griffin AM, Harrison BL, et al. (2018). “Breakthroughs in neuroactive steroid drug discovery”. Bioorganic & Medicinal Chemistry Letters. 28 (2): 61–70. doi:10.1016/j.bmcl.2017.11.043. PMID 29223589.
- ^ Martinez Botella G, Salituro FG, Harrison BL, Beresis RT, Bai Z, Blanco MJ, et al. (2017). “Neuroactive Steroids. 2. 3α-Hydroxy-3β-methyl-21-(4-cyano-1H-pyrazol-1′-yl)-19-nor-5β-pregnan-20-one (SAGE-217): A Clinical Next Generation Neuroactive Steroid Positive Allosteric Modulator of the (γ-Aminobutyric Acid)A Receptor”. Journal of Medicinal Chemistry. 60 (18): 7810–7819. doi:10.1021/acs.jmedchem.7b00846. PMID 28753313.
- ^ Saltzman J (4 August 2023). “FDA approves postpartum depression pill from two Cambridge drug firms”. The Boston Globe. Archived from the original on 6 August 2023. Retrieved 5 August 2023.
- ^ Althaus AL, Ackley MA, Belfort GM, Gee SM, Dai J, Nguyen DP, et al. (2020). “Preclinical characterization of zuranolone (SAGE-217), a selective neuroactive steroid GABAA receptor positive allosteric modulator”. Neuropharmacology. 181: 108333. doi:10.1016/j.neuropharm.2020.108333. PMC 8265595. PMID 32976892.
- ^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.
- ^ “FDA Approves Zurzuvae (zuranolone), the First and Only Oral Treatment Approved for Women with Postpartum Depression, and Issues a Complete Response Letter for Major Depressive Disorder” (Press release). Biogen Inc. 4 August 2023. Retrieved 4 August 2023 – via GlobeNewswire.
- ^ McKenzie H. “Sage Hints at Difficult Decisions After Zuranolone’s Rejection in MDD”.
- ^ Clayton AH, Lasser R, Parikh SV, Iosifescu DV, Jung J, Kotecha M, et al. (May 2023). “Zuranolone for the Treatment of Adults With Major Depressive Disorder: A Randomized, Placebo-Controlled Phase 3 Trial”. The American Journal of Psychiatry: appiajp20220459. doi:10.1176/appi.ajp.20220459. PMID 37132201. S2CID 258461851.
- ^ Deligiannidis KM, Meltzer-Brody S, Gunduz-Bruce H, Doherty J, Jonas J, Li S, et al. (2021). “Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial”. JAMA Psychiatry. 78 (9): 951–959. doi:10.1001/jamapsychiatry.2021.1559. PMC 8246337. PMID 34190962.
- ^ Bullock A, Kaul I, Li S, Silber C, Doherty J, Kanes SJ (2021). “Zuranolone as an oral adjunct to treatment of Parkinsonian tremor: A phase 2, open-label study”. Journal of the Neurological Sciences. 421: 117277. doi:10.1016/j.jns.2020.117277. PMID 33387701. S2CID 229333842.
External links
- Clinical trial number NCT04442503 for “A Study to Evaluate the Efficacy and Safety of SAGE-217 in Participants With Severe Postpartum Depression (PPD)” at ClinicalTrials.gov
- Clinical trial number NCT02978326 for “A Study to Evaluate SAGE-217 in Participants With Severe Postpartum Depression” at ClinicalTrials.gov
/////////Zuranolone, FDA 2023, APPROVALS 2023, Zurzuvae, postpartum depression , SAGE 217, SAGE-217, SAGE217
[H][C@@]1(CC[C@@]2([H])[C@]3([H])CC[C@]4([H])C[C@](C)(O)CC[C@]4([H])[C@@]3([H])CC[C@]12C)C(=O)CN1C=C(C=N1)C#N
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ABY 737
ABT-737
| Molecular Weight | 813.43 |
|---|---|
| Formula | C42H45ClN6O5S2 |
| CAS No. | 852808-04-9 |
ABT-737 is a small molecule drug that inhibits Bcl-2 and Bcl-xL, two members of the Bcl-2 family of evolutionarily-conserved proteins that share Bcl-2 Homology (BH) domains. First developed as a potential cancer chemotherapy,[1] it was subsequently identified as a senolytic (a drug that selectively induces cell death in senescent cells).[2]
The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion; Bcl-2 and Bcl-xL are anti-apoptotic proteins. Because many cancers have mutations in these genes that allow them to survive, scientists began working to develop drugs that would inhibit this pathway in the 1990s.[1] ABT-737 was one of the earliest of a series of drugs developed by Abbott Laboratories (now Abbvie) to target this pathway, based on their resolution of the 3D structure of Bcl-xL and studies using high-field solution nuclear magnetic resonance (NMR) that revealed how the BH domains of these proteins interacted with their targets.[1]
ABT-737 was superior to previous BCL-2 inhibitors given its higher affinity for Bcl-2, Bcl-xL and Bcl-w. In vitro studies showed that primary cells from patients with B-cell malignancies are sensitive to ABT-737.[3] In animal models, it improved survival, caused tumor regression, and cured a high percentage of mice.[4] In preclinical studies utilizing patient xenografts, ABT-737 showed efficacy for treating lymphoma and other blood cancers.[5]
Unfortunately, ABT-737 is not bioavailable after oral administration, leading to the development of navitoclax (ABT-263) as an orally-available derivative with similar activity on small cell lung cancer (SCLC) cell lines.[1][6] Navitoclax entered clinical trials,[1][6] and showed promise in haematologic cancers, but was stalled when it was found to cause thrombocytopenia (severe loss of platelets), which was discovered to be caused by the platelets’ requirement for Bcl-xL for survival.[1]
Subsequently, it was reported that ABT-737 specifically induces apoptosis in senescent cells in vitro and in mouse models.[2]
ABT-737, a BH3 mimetic, is a potent Bcl-2, Bcl-xL and Bcl-w inhibitor with EC50s of 30.3 nM, 78.7 nM, and 197.8 nM, respectively. ABT-737 induces the disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway. ABT-737 induces autophagy and has the potential for acute myeloid leukemia (AML) research.
PATENT
PATENT
CN113248415
PATENT
US20070015787
Journal of Medicinal Chemistry (2007), 50(4), 641-662
https://pubs.acs.org/doi/10.1021/jm061152t
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| Names | |
|---|---|
| Preferred IUPAC name4-{4-[(4′-Chloro[1,1′-biphenyl]-2-yl)methyl]piperazin-1-yl}-N-(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene-1-sulfonyl)benzamide | |
| Identifiers | |
| CAS Number | 852808-04-9 |
| 3D model (JSmol) | Interactive image |
| ChEBI | CHEBI:47575 |
| ChemSpider | 9403232 |
| PubChemCID | 11228183 |
| UNII | Z5NFR173NV |
| CompTox Dashboard (EPA) | DTXSID7042641 |
| showInChI | |
| showSMILES | |
| Properties | |
| Chemical formula | C42H45ClN6O5S2 |
| Molar mass | 813.43 g·mol−1 |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
References
- ^ Jump up to:a b c d e f Croce, Carlo M; Reed, John C (October 2016). “Finally, An Apoptosis-Targeting Therapeutic for Cancer”. Cancer Research. 76 (20): 5914–5920. doi:10.1158/0008-5472.CAN-16-1248. PMC 5117672. PMID 27694602.
- ^ Jump up to:a b Yosef, Reut; Pilpel, Noam; Tokarsky-Amiel, Ronit; Biran, Anat; Ovadya, Yossi; Cohen, Snir; Vadai, Ezra; Dassa, Liat; Shahar, Elisheva; Condiotti, Reba; Ben-Porath, Ittai; Krizhanovsky, Valery (2016). “Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL”. Nature Communications. 7: 11190. Bibcode:2016NatCo…711190Y. doi:10.1038/ncomms11190. PMC 4823827. PMID 27048913.
- ^ Vogler, Meike, et al. “Bcl-2 inhibitors: small molecules with a big impact on cancer therapy.” Cell Death & Differentiation 16.3 (2008): 360–367.
- ^ Oltersdorf, Tilman; Elmore, Steven W.; Shoemaker, Alexander R.; Armstrong, Robert C.; Augeri, David J.; Belli, Barbara A.; Bruncko, Milan; Deckwerth, Thomas L.; Dinges, Jurgen; Hajduk, Philip J.; Joseph, Mary K.; Kitada, Shinichi; Korsmeyer, Stanley J.; Kunzer, Aaron R.; Letai, Anthony; Li, Chi; Mitten, Michael J.; Nettesheim, David G.; Ng, ShiChung; Nimmer, Paul M.; O’Connor, Jacqueline M.; Oleksijew, Anatol; Petros, Andrew M.; Reed, John C.; Shen, Wang; Tahir, Stephen K.; Thompson, Craig B.; Tomaselli, Kevin J.; Wang, Baole; Wendt, Michael D.; Zhang, Haichao; Fesik, Stephen W.; Rosenberg, Saul H. (2005). “An inhibitor of Bcl-2 family proteins induces regression of solid tumours”. Nature. 435 (7042): 677–81. Bibcode:2005Natur.435..677O. doi:10.1038/nature03579. PMID 15902208. S2CID 4335635.
- ^ Hann CL, Daniel VC, Sugar EA, Dobromilskaya I, Murphy SC, Cope L, Lin X, Hierman JS, Wilburn DL, Watkins DN, Rudin CM (April 2008). “Therapeutic efficacy of ABT-737, a selective inhibitor of BCL-2, in small cell lung cancer”. Cancer Research. 68 (7): 2321–8. doi:10.1158/0008-5472.can-07-5031. PMC 3159963. PMID 18381439.
- ^ Jump up to:a b Hauck P, Chao BH, Litz J, Krystal GW (April 2009). “Alterations in the Noxa/Mcl-1 axis determine sensitivity of small cell lung cancer to the BH3 mimetic ABT-737”. Mol Cancer Ther. 8 (4): 883–92. doi:10.1158/1535-7163.MCT-08-1118. PMID 19372561. Retrieved 9 September 2019.
///////////ABT-737, ABT 737
CN(CC[C@@H](NC1=CC=C(C=C1[N+]([O-])=O)S(NC(C2=CC=C(C=C2)N3CCN(CC3)CC4=CC=CC=C4C5=CC=C(C=C5)Cl)=O)(=O)=O)CSC6=CC=CC=C6)C
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Tolebrutinib, SAR 442168
Tolebrutinib
SAR442168
- Treatment of Multiple Sclerosis (MS)
CAS 1971920-73-6
PRN 2246, example 3 [WO2016196840A1]
C26H25N5O3,
| 455.5 |
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one
(R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one
4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-
enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-
Tolebrutinib (R&D code SAR442168), developed by Principia and later acquired by Sanofi and included in its product line, Tolebrutinib is a BTK inhibitor used to treat cancer, autoimmune diseases such as multiple sclerosis and myasthenia gravis, inflammatory diseases and thromboembolic diseases, etc.,
Tolebrutinib is an orally bioavailable, brain-penetrant, selective, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), with potential immunomodulatory and anti-inflammatory activities. Upon oral administration, tolebrutinib is able to cross the blood-brain barrier and inhibits the activity of BTK both peripherally and in the central nervous system (CNS). This prevents the activation of the B-cell antigen receptor (BCR) signaling pathway, and the resulting immune activation and inflammation. The inhibition of BTK activity also prevents microglial inflammatory signaling in the CNS, and the resulting immune activation, neuroinflammation and neurodegeneration. BTK, a cytoplasmic tyrosine kinase and member of the Tec family of kinases, plays an important role in B lymphocyte development, activation, signaling, proliferation and survival. In addition to B cells, BTK is also expressed in innate immune cells, including macrophages and microglia, and plays an important role in the regulation of microglial inflammatory signaling.
BTK, a member of the Tec family non-receptor tyrosine kinases, is essential for B cell signaling downstream from the B-cell receptor. It is expressed in B cells and other hematopoietic cells such as monocytes, macrophages and mast cells. It functions in various aspects of B cell function that maintain the B cell repertoire (see Gauld S. B. et al., B cell antigen receptor signaling: roles in cell development and disease. Science,
296: 1641 -2. 2002.) B cells pay a role in rheumatoid arthritis (see Perosa F., et ai, CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. / Intern Med. 267:260-77. 2010 and Dorner T, et at. Targeting B cells in immune-mediated
inflammatory disease: a comprehensive review of mechanisms of action and identification of biomarkers. Pharmacol The 125:464-75. 2010 and Honigberg, L., et. ai, The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis. Clin. Immunol. 127 SI :S 111. 2008) and in other autoimmune diseases such as systemic lupus erythematosus and cancers (see Shlomchik M. J., et. ai, The role of B cells in lpr/lpr-induced autoimmunity. /. Exp Med. 180:1295-1306. 1994; Honigberg L. A., The Braton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc. Natl. Acad. Sci. 107: 13075-80. 2010; and Mina-Osorio P, et al., Suppression of
glomerulonephritis in lupus-prone NZB x NZW mice by RN486, a selective inhibitor of Bruton’s tyrosine kinase. Arthritis Rheum. 65: 2380-91. 2013).
There is also potential for BTK inhibitors for treating allergic diseases (see Honigberg, L., et. al., The selective BTK inhibitor PCI-32765 blocks B cell and mast cell activation and prevents mouse collagen indiced arthritis. Clin. Immunol. 127 SI :S111. 2008). It was noted that the irreversible inhibitor suppresses passive cutaneous anaphylaxis (PCA) induced by IgE antigen complex in mice. These findings are in agreement with those noted with BTK-mutant mast cells and knockout mice and suggest that BTK inhibitors may be useful for the treatment of asthma, an IgE-dependent allergic disease of the airway.
Accordingly, compounds that inhibit BTK would be useful in treatment for diseases such as autoimmune diseases, inflammatory diseases, and cancer.
PATENT
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016196840
Example 3
Synthesis of (R)-l-(l-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-lH- imidazo[4,5-c]pyridin-2(3H)-one
Into a 100-mL round-bottom flask, was placed (R)-4-amino-3-(4-phenoxyphenyl)-l-(piperidin-3-yl)-lH-imidazo[4,5-c]pyridin-2(3H)-one (150 mg, 0.37 mmol, 1.00 equiv), DCM-CH30H (6 mL), TEA (113 mg, 1.12 mmol, 3.00 equiv). This was followed by the addition of prop-2-enoyl chloride (40.1 mg, 0.44 mmol, 1.20 equiv) dropwise with stirring at OoC in 5 min. The resulting solution was stirred for 2 h at 0 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (30: 1). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column, XBridge Prep CI 8 OBD
Column,5um, 19*150mm; mobile phase, water with 0.05%TFA and ACN (25.0% ACN up to 45.0% in 8 min). 54.5 mg product of (R)-l-(l -acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-lH-imidazo[4,5-c]pyridin-2(3H)-one was obtained as a white solid. LC-MS m/z: 465.2 (M+l)
Step 2
Into a 25-mL round-bottom flask was placed tert-butyl (3R)-3-[4-[(E)-[(dimethy]amino)-methylidene]-amino]-2-oxo-3-(4-phenoxyphenyl)-lH,2H,3H-imidazo[4,5-c]pyridin-l -yl]piperidine- l-carboxylate (150 mg, 0.27 mmol, 1.00 equiv), 1,4-dioxane (6 mL), and hydrogen chloride (3 mL). The resulting solution was stirred overnight at 50° C. The reaction mixture was quenched with water. The pH of the solution was adjusted to 9 with sodium bicarbonate. The resulting solution was extracted with dichloromethane:CH3OH=10: 1 and the organic layers were combined. The resulting mixture was washed with sodium chloride and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (30: 1) to give 80 mg (74%) of 4-amino-3-(4-phenoxyphenyl)-l -[(3R)-piperidin-3-yl]-lH,2H,3H-imidazo[4,5-c]pyridin-2-one as a light yellow solid.
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/////////Tolebrutinib, SAR 442168, PRN 2246, GTPL10625, BTK’168, EX-A4699, BDBM50557487, WHO 11268, Multiple Sclerosis, (MS),
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RELACORILANT
Relacorilant
- Molecular FormulaC27H22F4N6O3S
- Average mass586.561 Da
CAS 1496510-51-0
Phase III
[(4aR)-1-(4-fluorophenyl)-6-(1-methylpyrazol-4-yl)sulfonyl-4,5,7,8-tetrahydropyrazolo[3,4-g]isoquinolin-4a-yl]-[4-(trifluoromethyl)pyridin-2-yl]methanone
релакорилант[Russian][INN]
ريلاكوريلانت[Arabic][INN]
瑞拉可兰[Chinese][INN]
- OriginatorCorcept Therapeutics
- ClassAntineoplastics; Fluorine compounds; Isoquinolines; Ketones; Organic sulfur compounds; Pyrazoles; Pyridines; Small molecules
- Mechanism of ActionGlucocorticoid receptor antagonists
- Orphan Drug StatusYes – Pancreatic cancer; Cushing syndrome
- Phase IIICushing syndrome; Ovarian cancer; Pancreatic cancer
- Phase IIFallopian tube cancer; Peritoneal cancer; Prostate cancer
- Phase I/IISolid tumours
- Phase IAdrenocortical carcinoma
Most Recent Events
- 09 Sep 2022Subgroup analysis efficacy data from a phase-II trial in Ovarian cancer presented at the 47th European Society for Medical Oncology Congress (ESMO-2022)
- 29 Jun 2022Phase-III clinical trials in Ovarian cancer (Combination therapy, Recurrent, Second-line therapy or greater) in USA (PO)
- 06 Jun 2022Corcept Therapeutics announces intentions to submit a NDA for Ovarian cancer
Relacorilant (developmental code name CORT-125134) is an antiglucocorticoid which is under development by Corcept Therapeutics for the treatment of Cushing’s syndrome.[1] It is also under development for the treatment of solid tumors and alcoholism.[1][2] The drug is a nonsteroidal compound and acts as an antagonist of the glucocorticoid receptor.[1] As of December 2017, it is in phase II clinical trials for Cushing’s syndrome and phase I/II clinical studies for solid tumors, while the clinical phase for alcoholism is unknown.[1]
Relacorilant is an orally available antagonist of the glucocorticoid receptor (GR), with potential antineoplastic activity. Upon administration, relacorilant competitively binds to and blocks GRs. This inhibits the activity of GRs, and prevents both the translocation of the ligand-GR complexes to the nucleus and gene expression of GR-associated genes. This decreases the negative effects that result from excess levels of endogenous glucocorticoids, like those seen when tumors overproduce glucocorticoids. In addition, by binding to GRs and preventing their activity, inhibition with CORT125134 also inhibits the proliferation of GR-overexpressing cancer cells. GRs are overexpressed in certain tumor cell types and promote tumor cell proliferation.
SCHEME
CLIP
https://europepmc.org/article/pmc/pmc8175224
Relacorilant (CORT125134)118) is being developed by Corcept Therapeutics, Inc. It is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that may benefit from the modulation of cortisol activity. In structural optimization, the introduction of a trifluoromethyl group to the 4-position on the pyridyl moiety was found to increase HepG2 tyrosine amino transferase assay potency by a factor of four. Relacorilant is currently being evaluated in a phase II clinical study in patients with Cushing’s syndrome.119)
2-Bromo-4-(trifluoromethyl)pyridine (17) prepared from (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one is employed as a key intermediate for the preparation of relacorilant as shown in Scheme 31.120)
Scheme31. Synthesis of relacorilant.118)
118) H. Hunt, T. Johnson, N. Ray and I. Walters (Corcept Therapeutics, Inc.): PCT Int. Appl. WO2013/177559 (2013).
119) H. J. Hunt, J. K. Belanoff, I. Walters, B. Gourdet, J. Thomas, N. Barton, J. Unitt, T. Phillips, D. Swift and E. Eaton: Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J. Med. Chem. 60, 3405–3421 (2017). [Abstract] [Google Scholar]
120) B. Lehnemann, J. Jung and A. Meudt (Archimica GmbH): PCT Int. Appl. WO 2007/000249 (2007).
PAPER
https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b00162
The nonselective glucocorticoid receptor (GR) antagonist mifepristone has been approved in the U.S. for the treatment of selected patients with Cushing’s syndrome. While this drug is highly effective, lack of selectivity for GR leads to unwanted side effects in some patients. Optimization of the previously described fused azadecalin series of selective GR antagonists led to the identification of CORT125134, which is currently being evaluated in a phase 2 clinical study in patients with Cushing’s syndrome.
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013177559
SYN
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Cushing’s syndrome (CS) is a metabolic disorder caused by chronic hypercortisolism. CS is associated with cardiovascular, metabolic, skeletal and psychological dysfunctions and can be fatal if left untreated. The first-line treatment for all forms of CS is a surgery. However, medical therapy has to be chosen if surgical resection is not an option or is deemed ineffective. Currently available therapeutics are either not selective and have side effects or are only available as an injection (pasireotide).
References
- ^ Jump up to:a b c d “Relacorilant – Corcept Therapeutics – AdisInsight”.
- ^ Veneris JT, Darcy KM, Mhawech-Fauceglia P, Tian C, Lengyel E, Lastra RR, Pejovic T, Conzen SD, Fleming GF (2017). “High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer”. Gynecol. Oncol. 146 (1): 153–160. doi:10.1016/j.ygyno.2017.04.012. PMC 5955699. PMID 28456378.
External links
| Clinical data | |
|---|---|
| Other names | CORT-125134 |
| Routes of administration | By mouth |
| Drug class | Antiglucocorticoid |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1496510-51-0 |
| PubChem CID | 73051463 |
| ChemSpider | 57617720 |
| UNII | 2158753C7E |
| KEGG | D11336 |
| Chemical and physical data | |
| Formula | C27H22F4N6O3S |
| Molar mass | 586.57 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI |
//////////////Relacorilant, Phase III , Orphan Drug, Cushing syndrome, Ovarian cancer, Pancreatic cancer, релакорилант , ريلاكوريلانت , 瑞拉可兰 ,
CN1C=C(C=N1)S(=O)(=O)N2CCC3=CC4=C(CC3(C2)C(=O)C5=NC=CC(=C5)C(F)(F)F)C=NN4C6=CC=C(C=C6)F
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MILADEMETAN
Milademetan
| Molecular Weight | 618.53 |
|---|---|
| Formula | C30H34Cl2FN5O4 |
| CAS No. | 1398568-47-2 |
Milademetan. hcl
Chemical Formula: C30H35Cl3FN5O4
Exact Mass: 617.1972
Molecular Weight: 654.99
Elemental Analysis: C, 55.01; H, 5.39; Cl, 16.24; F, 2.90; N, 10.69; O, 9.77
1398568-47-2 (free base) 1398569-75-9 (tosylate) 2095625-97-9 (tosylate hydrate) Milademetan HCl
DS3032b; DS-3032b; DS 3032b; DS3032; DS-3032; DS 3032; DS-3032b tosylate; Milademetan tosylate; Milademetan HCl
(3’R,4’S,5’R)-N-[(3R,6S)-6-carbamoyloxan-3-yl]-6”-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2”-oxo-1”,2”-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indole]-5′-carboxamide hydrochloride
orphan drug, UNII:R3I80TLN7S, миладеметан , ميلاديميتان , 米拉美坦
(3’R,4’S,5’R)-N-((3R,6S)-6-Carbamoyltetrahydro-2H-pyran-3-yl)-6”-chloro-4′-(2-chloro-3-fluoro-4-pyridinyl)-4,4-dimethyl-2”-oxo-1”,2”-dihydrodispiro(cyclohexane-1,2′-pyrrolidine-3′,3”-indole)-5′-carboxamide
milademetan
rolontis
SPI-2012
Milademetan, also known as DS-3032b or DS-3032, is a potent and selective MDM2 inhibitor with potential antineoplastic activity. Upon oral administration, MDM2 inhibitor DS-3032b binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. By preventing this MDM2-p53 interaction, the proteosome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis.
DS-3032 (Milademetan) is an orally available, potent and selective inhibitor of the p53-MDM2 (murine double minute 2) interaction. Milademetan binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. Milademetan is 10-fold more potent than the first-generation inhibitor nutlin-3a. By preventing this MDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis. DS-3032 is currently being evaluated in three phase 1 clinical trials for solid and hematological malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS).
- OriginatorRigel Pharmaceuticals
- DeveloperDaiichi Sankyo Inc; National Cancer Center Hospital East; Rain Therapeutics; University of Texas M. D. Anderson Cancer Center
- ClassAntineoplastics; Cyclohexanes; Indoles; Pyrrolidines; Small molecules
- Mechanism of ActionProto-oncogene protein c mdm2 inhibitors
- Orphan Drug StatusYes – Liposarcoma
- Phase IIILiposarcoma
- Phase IISarcoma; Solid tumours
- Phase I/IIAcute myeloid leukaemia
- Phase ILymphoma; Myelodysplastic syndromes
- PreclinicalMesothelioma
- No development reportedMultiple myeloma
- 10 Aug 2022Rain Therapeutics completes enrolment in phase-III clinical trials in Liposarcoma in (Inoperable/Unresectable, Metastatic disease, Second-line therapy or greater) in United Kingdom, Taiwan, Spain, Poland, South Korea, Italy, Hong Kong, Germany, Georgia, France, Canada, Belgium, Austria (PO) (NCT04979442)
- 09 Jun 2022Efficacy, adverse events and pharmacodynamics data from phase I/II trial in Acute myeloid leukemia presented at the 27th Congress of the European Haematology Association(EHA-2022)
- 04 May 2022Rain Therapeutics plans a phase I/II MANTRA-4 trial in Solid tumours (Combination therapy, Late-stage disease) in Second half of 2022
PATENT
WO2015033974
[Example 2]
Ethyl (3’R,4’S,5’R)-6”-chloro-4′-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2”-oxo 1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate
[0202]
[Chem. 58]
[0203]
(3E/Z)-6-chloro-3-(3-chloro-2-fluorobenzylidene)-1,3-dihydro-2H-indol-2-one ( WO 2006/091646) (98.7) under nitrogen atmosphere mg), (R)-BINAP (12.1 mg, 0.019 mmol), CuOAc (2.0 mg, 0.016 mmol), 4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester. (39.5 μL, 0.39 mmol) and a solution of triethylamine (6.8 μL, 0.049 mmol) in N,N-dimethylacetamide (2.0 mL) were added and stirred at room temperature for 22 hours. Ethyl acetate (2 mL), water (1 mL), and 20% aqueous ammonium chloride solution (1 mL) were added to the reaction mixture, and the mixture was vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2 mL each) and all the organic layers were combined and then washed with water three times (5 mL each). The obtained organic layer was concentrated under reduced pressure, ethyl acetate (6 mL) and silica gel (500 mg) were added to the residue, and the silica gel was separated by filtration. The filtrate was concentrated under reduced pressure, ethanol (1.0 mL) was added to the residue, water (1 mL) was added dropwise, and the mixture was stirred overnight at room temperature. The precipitated solid was filtered and dried under reduced pressure at 40° C. to obtain the title compound (137 mg, yield 82%, 94% ee) as a solid.
1H NMR (500 MHz, CDCl3): δ = 0.67 (s, 3H), 0.91 (s, 3H), 1.10-1.19 (m, 2H), 1.17 (t, J=7.3 Hz, 3H), 1.25-1.33 (m, 1H), 1.44- 1.72 (m, 3H), 1.87-2.01 (m, 1H), 3.16 (s, 1H), 4.07-4.21 (m, 2H), 4.52 (d, J = 8.5 Hz, 1H), 4.83 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 1.5Hz, 1H), 6.81-6.86 (m, 1H), 7.06 (dd, J = 8.3, 2.8 Hz, 1H), 7.10-7.16 (m, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 7.48-7.54 (m, 1H), 7.81 (s, 1H).
(HPLC conditions for optical purity determination)
カラム: CHIRALPAK OD-3R 4.6 × 150 mm, 3μm
Moving layer: 10mM Rinic acid buffer: MeCN = 40:60
Flow rate: 1.0 min/min
カラム Temperature: 40°C
Exhaust wavelength: 254 nm
Injection volume: 5 μL
Hold time: Labeling compound = 13.8 min, エナンチオマー= 12.9 min
[Example 11]
11-1) Effects of various asymmetric catalysts
[0230]
[Chem. 67]
[0231]
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one ( WO 2012 / 121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol%) in THF solution (10 times the volume), separately, Lewis acid (5 mol%) , an asymmetric ligand (6 mol %) and THF (10 times the amount) were stirred for 1 hour under a nitrogen atmosphere, a catalyst solution prepared was added, and the mixture was stirred at room temperature for 12 to 16 hours. After that, the resulting trans1 compound ((ethyl (3′S,4′R,5′S)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl) -4,4-dimethyl-2”-oxo-1”,2”-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3”-indole]-5′-carboxylate) Optical purity and HPLC yield were measured.
(HPLC conditions for measuring optical purity)
Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 µm
Mobile phase: 10 mM phosphoric acid buffer: MeCN = 40:60
Flow rate: 1.0 min/min
column Temperature: 40°C
Detection wavelength: 254 nm
Injection volume: 5 µL
Retention time: Title compound = 13.8 min, enantiomer = 12.9 min
Main results are shown in Table 1.
[0232]
[Table 1-1]
[Table 1-2]
[0233]
11-2) Effects of various solvents
[0234]
[Chem. 68]
[0235]
(3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one ( WO 2012 / 121361), 4,4-dimethylcyclohexanone (1.5 eq.), glycine ethyl ester (1.2 eq.), triethylamine (15 mol%), a solvent (10 times the amount), CuOAc (5 mol%), ( A catalyst solution prepared by stirring S)-BINAP (6 mol %) and a solvent (10 times the amount) under a nitrogen atmosphere for 1 hour was added, followed by stirring at room temperature for 21.5 hours. After that, by HPLC, the resulting trans2 compound (ethyl (3’S,4’R,5’S)-6”-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)- HPLC of 4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylate) Yields and optical purities were determined.
Table 2 shows the main results.
[0236]
[Table 2]
11-3) Examination of Cu(I) Lewis acid
PATENT
WO2014038606
WO2014038606 CLICK HERE
Example 1
[0062]
[Chem.3]
[0063]
(3′R,4′S,5′R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6″-chloro-4′-(2-chloro- 3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5 ‘
-Carboxamide The compound (35 mg, 0.24 mmol) obtained in Reference Example 2, Step 3 was added to a solution of the compound (100 mg, 0.20 mmol) obtained in Step 3 of Reference Example 1 in N,N-dimethylformamide (4 ml). , triethylamine (0.04 ml, 0.30 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46 mg, 0.24 mmol) were added. , and stirred for 1 hour at 50° C. After allowing to cool, the reaction solution was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by NH-silica gel column chromatography [chloroform:methanol=50:1 (v/v)]. After stirring for 24 hours at rt, the solvent was distilled off under reduced pressure to obtain 94 mg (76%) of the title compound as a solid.1H
– NMR (400 MHz, CDCl3 ) .) δ: 0.68 (3H, s), 0.95 (3H, s), 1.11-1.27 (2H, m), 1.35-1.81 (8H, m), 2.10-2.17 (1H, m), 2.25-2.32 (1H, m), 3.15(1H,t,J=10.5Hz), 3.27(1H,br s), 3.80(1H,dd,J=11.0,2.3Hz), 3.85-3.95(1H,m), 4.13(1H, ddd,J=10.8,4.5,1.3Hz),4.44(1H,d,J=9.2Hz),4.64(1H,d,J=9.2Hz),5.46(1H,d,J=3.7Hz),6.49( 1H,d,J=3.7Hz), 6.74(1H,d,J=1.8Hz), 7.07(1H,dd,J=8.2,1.8Hz), 7.31(1H,dd,J=8.2,2.3Hz), 7.48-7.52(2H,m),7.62(1H,s),8.05(1H,d,J=5.5Hz).MS
(ESI)m/z:618(M+H) +
Reference example 1
[0087]
[Chem.4]
[0088]
[Step 1] (3E/Z)-6-chloro-3-[(2-chloro-3-fluoropyridin-4-yl)methylene]-1,3-dihydro-2H-indol-2-one
6-chloro -1,3-dihydro-2H-indol-2-one (2.20 g, 13.11 mmol) and 2-chloro-3-fluoroisonicotinaldehyde (2.20 g, 13.8 mmol) in methanol (130 ml). , N,N-diisopropylethylamine (0.46 ml, 2.63 mmol) was added, and the mixture was heated under reflux for 16 hours. After standing to cool, the precipitate was collected by filtration, washed with cold methanol and dried to obtain 3.37 g (83%) of the title compound as a solid.
MS(APCI) m/z: 309(M+H) + .
[0089]
[Step 2] (3′S,4′R,7′S,8′S,8a′R)-6″-chloro-8′-(2-chloro-3-fluoropyridin-4-yl)-4 ,4-dimethyl-3′,4′-diphenyl-3′,4′,8′,8a′-tetrahydro-1′H-dispiro[cyclohexane-1,6′-pyrrolo[2,1-c][1 ,4]oxazine-7′,3″-indole]-1′,2″(1″H)
-dione Under a nitrogen atmosphere, the compound obtained in Step 1 (1.86 g, 6.00 mmol), (5R,6S )-5,6-diphenylmorpholin-2-one (1.67 g, 6.60 mmol) and 4,4-dimethylcyclohexanone (0.83 g, 6.60 mmol) in tetrahydrofuran (30 ml) was added with diethyl boron trifluoride. An ether complex (0.15 ml, 1.20 mmol) and molecular sieve 4A (powder) (3 g) were added, and the mixture was heated and stirred at 70° C. for 7 days. After allowing to cool, insoluble matter was removed by filtration through celite, and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography [n-hexane:ethyl acetate=4:1→1:1 (v/v)] to obtain 3.39 g (84%) of the title compound as a solid. rice field.
1 H-NMR (400 MHz, CDCl3) δ: 0.21 (3H, s), 0.53 (3H, s), 0.89-1.08 (3H, m), 1.28-1.43 (3H, m), 1.73-1.81 (1H, m), 2.23-2.33 (1H, m), 4.58 (1H, d, J = 11.0Hz), 4.86 (1H, d, J = 3.2Hz), 5.31 (1H, d, J = 11.0Hz), 6.25 (1H, d, J = 8.3Hz) ,6.67(1H,dd,J=8.3,1.8Hz),6.72-6.77(2H,m),6.93(1H,d,J=1.8Hz),7.04-7.17(6H,m),7.18-7.25(3H ,m),7.79(1H,t,J=4.6Hz),7.99(1H,s),8.29(1H,d,J=5.0Hz).MS
(APCI)m/z:670(M+H) + .
[0090]
[Step 3] (4′S,5′R)-6″-chloro-4′-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2″-oxo-1″ ,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid
The compound obtained in step 2 (630 mg, 0.94 mmol) was treated with acetonitrile (10 ml). Dissolve in water (4 ml), add potassium carbonate (130 mg, 0.94 mmol) and heat under reflux for 16 hours at 85° C. After allowing to cool, add anhydrous magnesium sulfate (113 mg, 0.94 mmol) and stir at room temperature for 15 minutes. After extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. (2-chloro-3-fluoropyridin-4-yl)-1′-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2″-oxo-1″ ,2″-dihydrodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indole]-5′-carboxylic acid (650 mg, 100%) was obtained as a solid [MS (ESI) m/z :688(M+H) +]. The resulting carboxylic acid (650 mg, 0.94 mmol) was dissolved in methanol (30 ml) and water (8 ml), and diammonium cerium (IV) nitrate (1.55 g, 2.82 mmol) was added under ice-cooling. Stir at room temperature for 30 minutes. Potassium carbonate (780 mg, 5.64 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. After removing the insoluble matter by filtration through celite, the filtrate was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [chloroform:methanol=20:1→4:1 (v/v)] to obtain 152 mg (33%) of the title compound as a solid. .
1 H-NMR (500 MHz, CD 3 OD) δ: 0.74 (3H, s), 0.9 (3H, s), 1.29-1.44 (2H, m), 1.48-1.58 (2H, m), 1.64-1.76 (1H ,m),1.94-2.02(1H,m),2.11(1H,ddd,J=14.0,14.0,4.0Hz),2.43-2.53(1H,m),5.07(1H,d,J=10.3Hz), 5.32(1H,d,J=10.3Hz),6.84(1H,d,J=1.7Hz),7.16(1H,dd,J=8.3,2.0Hz),7.63(1H,dd,J=8.0,2.3Hz) ),7.75(1H,t,J=5.2Hz),8.15(1H,d,J=5.2Hz).
MS(ESI)m/z:492(M+H) + .
[0091]
Reference example 2
[0092]
[Chem.5]
[0093]
[Step 1] Methyl 2,6-anhydro-3,4,5-trideoxy-5-(dibenzylamino)-L-erythro
-hexonate 2,6-anhydro-3,4,5-trideoxy-5-( dibenzylamino)-L-erythro-hexonate methyl 2,6-anhydro-3,4,5-trideoxy-5-(dibenzylamino)-L-erythro-hexonate (1.60 g, 4.70 mmol) was The mixture was dissolved in methanol (30 ml), 1N aqueous sodium hydroxide solution (10 ml) was gradually added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Dowex 50W-X8 was added to the reaction mixture to adjust the pH to 5 to 6, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1.7 g (100%) of the title compound as a solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.18-1.26(1H,m), 1.36-1.48(1H,m), 1.79-1.97(2H,m), 2.62(1H,t,J=11.0Hz) ,3.18(1H,t,J=10.4Hz),3.40(1H,d,J=11.5Hz),3.51-3.61(4H,m),3.90-3.99(1H,m),7.12-7.38(10H,m ).
MS(ESI)m/z:326(M+H) + .
[0094]
[Step 2] (2S,5R)-5-(dibenzylamino)tetrahydro-2H-pyran-2-carboxamide
The compound (870 mg, 2.67 mmol) obtained in Step 1 above was dissolved in N,N-dimethylformamide (30 ml). 1-hydroxybenzotriazole (361 mg, 2.67 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (614 mg, 3.20 mmol) were added and stirred at room temperature for 15 minutes. Ammonium chloride (285 mg, 5.44 mmol) and N,N-diisopropylethylamine (1.86 ml, 10.7 mmol) were added and stirred at room temperature for 8 hours. After diluting with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 495 mg (57%) of the title compound as a solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.35-1.45 (1H, m), 1.60-1.70 (1 H, m), 2.10-2.18 (1 H, m), 2.21-2.28 (1 H, m), 2.76 ( 1H,tt,J=11.4,4.0Hz),3.44(1H,t,J=10.9Hz),3.67(4H,q,J=14.2Hz),3.71-3.73(1H,m),4.04(1H,dq ,J=11.0,2.1Hz),5.35(1H,s),6.40(1H,s),7.21-7.36(10H,m).MS
(ESI)m/z:325(M+H) + .
[0095]
[Step 3] (2S,5R)-5-aminotetrahydro-2H-pyran-2-carboxamide
The compound (490 mg, 1.51 mmol) obtained in Step 2 above was dissolved in ethanol (10 ml) and treated with 20% palladium hydroxide. (100 mg) was added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After removing the catalyst by filtration through celite, the filtrate was distilled off under reduced pressure and dried to obtain 215 mg (99%) of the title compound as a solid.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.11-1.22(1H,m), 1.25-1.35(1H,m), 1.83-1.91(2H,m), 2.51-2.60(1H,m), 2.90(1H,t,J=10.5Hz),3.52(1H,d,J=11.9Hz),
3.78-3.84 (1H,m),6.99(1H,br s),7.09(1H,br s). (ESI) m/z: 145(M+H) + .
PATENT
WO2012121361
PATENT
WO2015033974
PAPER
https://pubs.acs.org/doi/10.1021/acs.oprd.2c00192
Abstract
Herein, we report the structure and synthesis of the potent MDM2-p53 inhibitor BI-0282. The complex spirooxindole scaffold bearing four stereocenters embedded in a rigid polycyclic ring-system was effectively prepared on a multi-gram scale in only five synthesis steps employing a three-component 1,3-dipolar cycloaddition and a late-stage Davis–Beirut reaction as key steps.
Compound 1
Intermediate 10 (28.8 g, 44.8 mmol) is dissolved in isopropanol (300 mL) and a solution of potassium hydroxide (39.0 g, 694.9 mmol) in water (95 mL) is slowly added. After stirring for 16 h at ambient temperature, the solvents are partially removed under reduced pressure. The residue is diluted with ethyl acetate and treated with a diluted aqueous solution of citric acid. After extraction of the aqueous layer with ethyl acetate, the organic layers are combined, dried with sodium sulfate, and the solvent is removed under reduced pressure. Purification by normal phase column chromatography using dichloromethane and methanol as solvents yields rac-1 (25.8 g, 43.5 mmol) in 70% yield as an amorphous white solid.
Chiral SFC and subsequent purification by reversed phase column chromatography using acetonitrile and methanol as solvents furnishes 1 (BI-0282).
Rac-1 (60 g, 93,3 mmol) was separated by chiral SFC and reversed phase column chromatography to obtain 1 (24.4 g, 40,0 mmol, 43%) as an amorphous white solid.
Chiral HPLC (CHIRALPAK, heptane/isopropanol/trifluoroacetic acid = 70/30/0.1, flow rate 1.0 mL/min, I = 240 mM) tR = 7.8 min (1), and 11.1 min (ent-1). Preparative SFC (CHIRALPAK, carbon dioxide/(isopropanol + 1% diethylamine) = 70/30, flow rate 300 g/min, I = 290 nM).
1H NMR (500 MHz, DMSO-d6): δ 12.64 (br s, 1H), 10.29 (s, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.83 Hz, 2H), 7.29–7.36 (m, 1H), 7.26 (d, J = 7.88 Hz, 1H), 7.21 (dd, J = 1.26, 8.83 Hz, 1H), 7.12 (t, J = 8.04 Hz, 1H), 6.92 (dd, J = 1.89, 7.88 Hz, 1H), 6.48 (d, J = 1.89 Hz, 1H), 5.86 (t, J = 9.14 Hz, 1H), 4.59–4.68 (m, 1H), 4.52 (dd, J = 7.88, 11.35 Hz, 1H), 4.23–4.32 (m, 1H), 4.20 (d, J = 10.09 Hz, 1H), 2.27 (dd, J = 7.57, 13.08 Hz, 1H), 2.13 (dd, J = 5.83, 13.08 Hz, 1H), 0.47–0.62 (m, 1H), 0.26–0.37 (m, 1H), 0.11–0.20 (m, 1H), −0.04 to 0.04 (m, 1H), −0.25 (s, 1H).
13C{1H} NMR (125 MHz, DMSO-d6): δ 177.5, 168.1, 156.1 (d, 1JC,F = 248.7 Hz), 146.3, 145.3, 144.0, 134.1, 130.3, 129.7, 129.5, 126.8, 126.7, 125.4 (d, 3JC,F = 4.4 Hz), 123.5 (d, 2JC,F = 13.2 Hz), 122.5, 120.0, 119.9, 119.7 (d, 2JC,F = 18.3 Hz), 118.7, 110.0, 107.3, 76.4, 69.2, 57.5, 56.8, 54.2, 51.2, 11.6, 5.5, 4.1.
HRMS (ESI) m/z: [M + H]+ calcd for C30H24Cl2FN4O4, 593.1153; found, 593.1165.
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Milademetan is under investigation in clinical trial NCT02319369 (Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)).
- [1]. ARYL SULFONOHYDRAZIDES. WO 2017069289 A1.[2]. M.M. Gounder, et al. Milademetan, an oral MDM2 inhibitor, in well-differentiated/dedifferentiated liposarcoma: results from a phase 1 study in patients with solid tumors or lymphomas. European Journal of Cancer 138S2 (2020) S1–S62.[3]. Li, Yangbing, et al. Development of novel PROTAC Small-Molecule Degraders of MDM2 Protein and Peptidomimetic Inhibitors Targeting WDR5-MLL1 Protein-Protein Interaction.[4]. Viktor Arnhold, et al. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. ncotarget. 2018 Jan 5; 9(2): 2304–2319.
/////////Milademetan, DS3032b, DS-3032b, DS 3032b, DS3032, DS-3032, DS 3032, DS-3032b tosylate, Milademetan tosylate, Milademetan HCl, orphan drug, UNII:R3I80TLN7S, миладеметан , ميلاديميتان , 米拉美坦
CC1(C)CCC2(CC1)N[C@H]([C@H](C1=C(F)C(Cl)=NC=C1)[C@]21C(=O)NC2=CC(Cl)=CC=C12)C(=O)N[C@@H]1CC[C@H](OC1)C(N)=O
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Firibastat
_648927-86-0.png)
Firibastat
- Molecular FormulaC8H20N2O6S4
- Average mass368.514 Da
368.5
RB 150
Qgc-001(racemate)
UNII-PD5EII1F9A
Firibastat, (+/-)-
PD5EII1F9A
3-amino-4-[(2-amino-4-sulfobutyl)disulfanyl]butane-1-sulfonic acid
1-Butanesulfonic acid, 4,4′-dithiobis(3-amino-
3-Amino-4-((2-amino-4-sulfo-butyl)disulfanyl)butane-1-sulfonic acid
cas 721392-96-7, RACEMIC
CAS 648927-86-0, (S)-3-amino-4-(((S)-2-amino-4-sulfobutyl)disulfaneyl)butane-1-sulfonic acid
фирибастат[Russian][INN]
فيريباستات[Arabic][INN]
(3S,3’S)-4,4′-Disulfanediylbis(3-aminobutane-1-sulfonic acid)
firibastatum
фирибастат
فيريباستات
非立巴司他[Chinese]
SCHEME
SEE AT END OF PAGE
PAPER
Journal of Labelled Compounds & Radiopharmaceuticals (2004), 47(13), 997-1005
PATENT
https://patents.google.com/patent/WO2020084131A1/en
PATENT
WO2012045849
EXAMPLES
Example 1: Synthesis of compound I from (S) ethyl 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butanoate
Step (a): (S) neopentyl 3-(benzylox carbonylamino) 4-hydroxybutane 1-sulfonate B
B
(S) ethyl 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butanoate A (41.55g, 100.0 mmol, 1.0 eq.) is added dropwise onto a 2M solution of LiBH4 in THF (50 mL, 44.8 g, 100.0 mmol, 1.0 eq.). The addition is performed at room temperature over a 3 hrs period. At the end of the addition, the mixture is stirred at room temperature until conversion is complete (A<1%). Addition of toluene, followed by hydrolysis with HC1, washings of the organic layer with NaHC03 and water, and concentration under vacuum lead to the desired product as a pale yellow oil in quantitative yield (ee = 98%), which slowly crystallises at room temperature in 4 or 5 days.
As B was found to have a very low melting point by DSC analysis, it was not possible to isolate it as a solid by simple crystallisation. It was decided to let it in solution and use it without further purification in the following step.
Step (b): (S) neopentyl 3-(benzyloxycarbonylamino) 4-(methylsulfonyloxy)butane 1-sulfonate
C
C
A solution of B (57.64 g, 154.34 mmol, 1.0 eq.) in toluene (115 mL, 2.0 vol.) is diluted with MTBE (173 mL, 3.0 vol.) at room temperature. Mesyl chloride (17.9 mL, 26.5 g, 231.50 mmol, 1.5 eq.) is then added at room temperature and the homogeneous mixture is cooled to 10°C. The addition of triethylamine (43.0 mL, 31.2 g, 308.67 mmol, 2.0 eq.) is performed at T<20°C. At the end of the addition, the mixture is stirred at 10°C until conversion is complete (B<1%). After hydrolysis with diluted HCl, the organic layer is washed with NaHC03, water and brine, followed by a partial concentration under reduced pressure. The corresponding mesylate is then crystallised by addition of heptanes (5.0 vol.) at 40°C. After cooling, filtration and drying, the expected product is isolated as a whitish solid in 92.5% yield and with a very high chemical purity (98%).
Step (c): (S) 2-(benzyloxycarbonylamino) 4-(neopentyloxysulfonyl)butyl thioacetate D
D
A solution of mesylate C (81.3 g, 180.05 mmol, 1.0 eq.) in acetone (203 mL, 2.5 vol.) is added dropwise to a suspension of potassium thioacetate (41.1 g, 360.1 mmol, 2.0 eq.) in acetone (203 mL, 2.5 vol.) at room temperature and over a period of 2 hrs. The reaction mixture is stirred at room temperature until conversion is complete (C<1%). After filtration of the salts and addition of toluene (4.0 vol.), acetone is removed by distillation under reduced pressure at 25°C. The solution is then treated with active charcoal and concentrated to 2.0 volumes. Slow addition of heptane (5.0 vol.) at room temperature, followed by cooling at 0°C, filtration and drying at 45°C, provides the expected product as a whitish solid in 78.2% yield and with a very high chemical purity (98%).
Step (d): (3S,3S’) neopentyl 4,4′-disulfanediylbis(3-(benzyloxycarbonylamino)butane 1-sulfonate) E
E
A solution of D (59.16 g, 137.1 mmol, 1.0 eq.) suspended in ethanol (203 mL, 2.5 vol.) is cooled to 0°C. 20% sodium hydroxide (25.1 mL, 150.8 mmol, 1.1 eq.) diluted with water
(16.9 mL, 0.285 vol.) is then added dropwise to the suspension by keeping the temperature below 10°C. The reaction mixture is warmed to room temperature and stirred until conversion is complete (D<1%). The intermediate thiol reacts at room temperature with a solution of iodine (20.9 g, 82.3 mmol, 0.6 eq.) in ethanol (118 mL, 2.0 vol.). The reaction is complete at the end of the addition of the oxidizing agent. After addition of a Na2S205 (13.0 g, 68.5 mmol, 0.5 eq.) aqueous solution (118 mL, 2.0 vol.) to reduce the excess of residual iodine, ethanol is removed by distillation under reduced pressure at 40°C. Addition of water (3.0 vol.) at room temperature, followed by cooling at 0°C, filtration and drying at 45-50°C, provides the expected dimer as a white solid in 98.3% yield and with a very high chemical purity (97.0%). The amount of iodide ions, coming from the reduction of iodine, is checked in the sample by potentiometric assay.
E°(Ag+/Ag(s))=0.80V
KsAgi=1.5.10“16
[AgNO3]=0.1N
Electrode: E=E°(Ag+/Ag(s))+0.061og[Ag+]
E=E°(Ag+/Ag(s))+0.061og (Ksi/[L])
Assay: [T] decreases and E increases
LOD=l mg
Four further washings with water are performed until no more iodide ions are detected. The results are presented in table 2.
Table 2.
Step (e): (3S,3S’) 4,4′-disulfanediylbis(3-aminobutane 1-sulfonic acid) compound I
4
Compound I
A solution of E (44.0 g, 56.6 mmol, 1.0 eq.) in TFA (220 mL, 5.0 vol.) and anisole (44 mL, 1.0 vol.) is heated to reflux (75°C) and the reaction mixture is stirred in these conditions until conversion is complete (E<1%). TFA is removed by distillation under reduced pressure at 50°C. Slow addition of MTBE (5.0 vol.) at room temperature makes the expected product precipitate. After trituration, filtration and washing with MTBE (1.0 vol.), the crude solid is suspended in methanol (220 mL, 5.0 vol.). New trituration, filtration and washing with MTBE (1.0 vol.), followed by drying under reduced pressure, provides compound I as a white solid in 92.5% yield.
NMR: 1H (solvent D20, 400 MHz, ppm): 4.70 (s, 6H, ¾); 3.77 (m, 2H, H2); 3.14 (dd, 2H, Hi); 2.98 (dd, 4H, H4); 2.86 (dd, 2H, Hi); 2.13 (m, 4H, H3). 13C (solvent D20, 100 MHz, ppm): 49.4 (2C, C2); 46.6 (2C, C4); 38.3 (2C, C ; 26.9 (2C, C3).
////////
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- OriginatorCNRS; INSERM; University Paris Descartes
- DeveloperQuantum Genomics
- ClassAmines; Aminopeptidases; Antihypertensives; Cardiovascular therapies; Disulfides; Heart failure therapies; Metalloexopeptidases; Small molecules; Sulfonic acids
- Mechanism of ActionGlutamyl aminopeptidase inhibitors
- Orphan Drug StatusNo
- New Molecular EntityYes
- Phase IIIHypertension
- Phase IIChronic heart failure; Left ventricular dysfunction
- 28 Mar 2022No recent reports of development identified for phase-I development in Hypertension(In volunteers) in United Kingdom (PO, Tablet)
- 25 Nov 2021Firibastat licensed to Teva in Israel
- 11 Oct 2021Quantum Genomics plans a phase III trial for Heart failure
////////Firibastat, фирибастат , فيريباستات , firibastatum, фирибастат ,فيريباستات ,非立巴司他 , rb 150, (+/-)-QGC-001, qgc 001,
C(CS(=O)(=O)O)C(CSSCC(CCS(=O)(=O)O)N)N
Enobosarm
Enobosarm
- Molecular FormulaC19H14F3N3O3
- Average mass389.328 Da
(2S)-3-(4-Cyanophenoxy)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide
(2S)-3-(4-Cyanophénoxy)-N-[4-cyano-3-(trifluorométhyl)phényl]-2-hydroxy-2-méthylpropanamide
841205-47-8[RN]
GTx-024, MK 2866, Ostarine[Trade name]
Enobosarm, also known as ostarine or MK-2866, is an investigational selective androgen receptor modulator (SARM) developed by GTx, Inc. for the treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merck & Company.
Chemistry
According to a 2009 paper authored by GTx, “Readers are cautioned to note that the name ostarine is often mistakenly linked to the chemical structure of [S-4], which is also known as andarine. The chemical structure of ostarine has not been publicly disclosed.”[2] A 2009 review stated “Recently, GTx disclosed that compound 5 had advanced into clinical trials. The patent application described detailed data in an initial proof-of-concept Phase IIa clinical trial. It is not explicitly stated that compound 5 is Ostarine (MK-2866).[3]
As of 2012, the mechanism of action of Enobosarm is still being debated and requires further investigation.[4]
Enobosarm is in phase II clinical studies for the treatment of metastatic breast cancer. It has been in phase III clinical trials for the treatment of muscle wasting in patients with non-small cell lung cancer. However, this research has been discontinued.
Enobosarm was discovered by University of Tennessee, then licensed to GTx later. It was granted fast track designation by FDA in 2013 for treatment of muscle wasting in patients with non-small cell lung cancer. Route 1
2. US20100249228A1.
3. US2014080905A1.
4. US20070173546A1. Route 2
1. US20070123563A1.2. US20100249228A1.
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/////////////////////////////////////////////////////////////////////////////
| Clinical data | |
|---|---|
| Other names | GTx-024; MK-2866; Ostarine; S-22[1] |
| Routes of administration | By mouth |
| ATC code | none |
| Legal status | |
| Legal status | US: Investigational New Drug |
| Pharmacokinetic data | |
| Elimination half-life | 24 hours[citation needed] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 841205-47-8 |
| PubChem CID | 11326715 |
| ChemSpider | 9501667 |
| UNII | O3571H3R8N |
| KEGG | D10221 |
| CompTox Dashboard (EPA) | DTXSID30233006 |
| Chemical and physical data | |
| Formula | C19H14F3N3O3 |
| Molar mass | 389.334 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| Melting point | 132 to 136 °C (270 to 277 °F) |
| showSMILES | |
| showInChI | |
History
GTx Incorporated was founded in Memphis in 1997 and licensed rights to enobosarm from the University of Tennessee Research Foundation; the SARM compounds were invented by James T. Dalton, Duane D. Miller, Karen A. Veverka and their research teams at Ohio State University, the University of Tennessee and GTx, respectively.[5]
By 2007, enobosarm was in a Phase II trial, and that year GTx signed an exclusive license agreement for its SARM program with Merck & Co.[6] The companies ended the deal in 2010.[7]
In August 2011, there was a double-blind, placebo controlled phase II trial that focused on elderly men and postmenopausal women which concluded that Enobosarm showed statistically significant improvements in total lean body mass and physical function without the negative side effects that are normally present with steroids.[8]
In August 2013, GTx announced that enobosarm had failed in two Phase III clinical trials to treat wasting in people with lung cancer.[9] The company had invested around $35 million in the development of the drug.[10] The company said at that time that it planned to pursue approval of enobosarm in Europe; the company was also still developing GTx-758 for castration-resistant prostate cancer.[11]
In 2016, GTx began Phase II trials, to see if enosobarm might be effective to treat stress urinary incontinence in women.[12]
In 2018, GTx announced the Phase II trials on Enobosarm’s efficacy on stress urinary incontinence[13] in women failed to achieve its primary endpoint in the ASTRID Trial.
Health effects
The FDA has warned that SARMs can have serious side effects ranging from risk of heart attack to stroke and liver damage.[14]
Society and culture
Doping
SARMs including Enobosarm may be and have been used by athletes to assist in training and increase physical stamina and fitness, potentially producing effects similar to anabolic steroids. For this reason, SARMs were banned by the World Anti-Doping Agency in January 2008, despite no drugs from this class yet being in clinical use, and blood tests for all known SARMs have been developed.[15][16] There are a variety of known cases of doping in sports with enobosarm by professional athletes.
Further information: List of doping in sport cases § Enobosarm
In May 2017, Dynamic Technical Formulations voluntarily recalled all lots of Tri-Ton, a dietary supplement that the USFDA tested and found to contain Enobosarm and andarine.[17]
In October 2018, UFC fighter Sean O’Malley tested positive for Enobosarm and was suspended by the Nevada State Athletic Commission and USADA for six months. O’Malley tested positive again on May 25, 2019 and was suspended for nine months by the same agencies. USADA determined that none of O’Malley’s positive tests were consistent with intentional use and he was allowed to compete at UFC 248 as long as he kept his levels below the threshold of 100 ng/ml.[18]
On January 7, 2019, the College National Football Championship was played between University of Alabama and Clemson University. Prior to the College Football National Championship game, three Clemson players who were suspended — Dexter Lawrence, Braden Galloway and Zach Giellaall — tested positive for a substance known as Enobosarm (ostarine). On June 23, 2019 Clemson did not release ostarine investigation findings, citing privacy law.[19]
In July 2019, National Football League player Taylor Lewan failed a drug test for Enobosarm, which Lewan claimed he ingested accidentally as an unlabeled ingredient in a supplement.[20]
On October 23, 2020, the Union Cycliste Internationale (UCI) announced that the Italian rider Matteo Spreafico has been notified of two adverse analytical findings (AAFs) for Enobosarm in two samples collected during the Giro d’Italia on 15–16 October 2020.[21]
On July 6, 2021, during the 2020 Summer Olympics, Brazil women’s national volleyball team player Tandara was temporarily suspended for testing positive for Ostarine. The test was carried out and identified by the Brazilian Doping Control Authority (ABDC).[22]
On August 12, 2021, after the 2020 Summer Olympics, Chijindu “CJ” Ujah, A member of the silver medal-winning British 4×100 relay team was temporarily suspended for testing positive for both Ostarine and S-23. The sample was collected post event by the International Testing Agency and confirmed two days later as positive. The case was referred to the anti-doping division of the Court of Arbitration for Sport.[23] Finally in February 2022, Great Britain were stripped of their silver medal.[24]
In October 2021, two Thoroughbred horses named Arafat and Komunist tested positive for ostarine after races at Woodbine Racetrack. In a decision of the Alcohol and Gaming Commission of Ontario issued May 30, 2022, the horses were declared unplaced in the races in question, and their trainer Robert Gerl was fined $100,000 (as well as forfeiting prize money) and suspended from racing for 20 years.[25]
In May 2022, National Football League Wide Receiver DeAndre Hopkins was suspended six games without pay by the NFL for violating the league’s performance-enhancing drug policy. According to Hopkins, he tested positive for ostarine.[26]
Wider use
In recent years, ostarine and related substances have increasingly become used by the general public as “gym supplements” such as pre-workout or lifestyle drugs, rather than as an aid to performance in athletic or bodybuilding competitions. In 2018, analysis of a fatberg from a sewer in central London showed ostarine to be the most abundant pharmaceutical drug detected, and was present at higher concentration than recreational drugs such as MDMA and cocaine. While this isolated result may not be representative of overall levels of use, for ostarine to be detectable in sewer deposits reflects significant levels of ostarine use in the area close to where the sample was collected.[27]
See also
References
- ^ “Enobosarm – GTx”. Adis Insight. Springer Nature Switzerland AG. Retrieved 25 April 2018.
- ^ Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, et al. (June 2009). “Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit”. Journal of Medicinal Chemistry. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
- ^ Zhang X, Lanter JC, Sui Z (September 2009). “Recent advances in the development of selective androgen receptor modulators”. Expert Opinion on Therapeutic Patents. 19 (9): 1239–58. doi:10.1517/13543770902994397. PMID 19505196. S2CID 46186955. The first quoted sentence is cited to Published PCT application WO2008127717
- ^ Dubois V, Laurent M, Boonen S, Vanderschueren D, Claessens F (May 2012). “Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions”. Cellular and Molecular Life Sciences. 69 (10): 1651–67. doi:10.1007/s00018-011-0883-3. PMID 22101547. S2CID 17276140.
- ^ WO 2005120483, Dalton JT, Mille DD, Veverka KA, “Selective androgen receptor modulators and methods of use thereof”, published 22 December 2005, assigned to University of Tennessee Research Foundation
- ^ Nagle M (7 November 2007). “Merck flexes muscle with GTx deal”. Outsourcing Pharma.
- ^ Swanekamp K (15 March 2010). “Merck And GTx Go Their Separate Ways”. Forbes.
- ^ Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. (September 2011). “The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial”. Journal of Cachexia, Sarcopenia and Muscle. 2 (3): 153–161. doi:10.1007/s13539-011-0034-6. PMC 3177038. PMID 22031847.
- ^ “Enobosarm fails endpoints in Ph III study”. The Pharma Letter. 20 August 2013.
- ^ Sheffield M (April 4, 2014). “Steiner resigns from GTx”. Memphis Business Journal.
- ^ Garde D (4 April 2014). “GTx’s CEO finds the door as the company moves on from a PhIII failure”. FierceBiotech.
- ^ “GTx begins Phase II trial of enobosarm to treat women with stress urinary incontinence”. Drug Development Technology. 14 January 2016. Archived from the original on 22 June 2016.
- ^ “GTx’s Enobosarm Fails Phase II Trial in Stress Urinary Incontinence; Stock Plunges 90%+”. Genetic Engineering & Biotechnology News. Retrieved 1 August 2019.
- ^ “FDA In Brief: FDA warns against using SARMs in body-building products”. Retrieved 1 August 2019.
- ^ Thevis M, Kohler M, Schlörer N, Kamber M, Kühn A, Linscheid MW, Schänzer W (May 2008). “Mass spectrometry of hydantoin-derived selective androgen receptor modulators”. Journal of Mass Spectrometry. 43 (5): 639–50. Bibcode:2008JMSp…43..639T. doi:10.1002/jms.1364. PMID 18095383.
- ^ Thevis M, Kohler M, Thomas A, Maurer J, Schlörer N, Kamber M, Schänzer W (May 2008). “Determination of benzimidazole- and bicyclic hydantoin-derived selective androgen receptor antagonists and agonists in human urine using LC-MS/MS”. Analytical and Bioanalytical Chemistry. 391 (1): 251–61. doi:10.1007/s00216-008-1882-6. PMID 18270691. S2CID 206899531.
- ^ “Dynamic Technical Formulations, LLC. Issues a Voluntary Nationwide Recall of Tri-Ton Due to the Presence of Andarine and Ostarine”. U.S. Food & Drug Administration. May 19, 2017.
- ^ Raimondi M (January 22, 2020). “NSAC: Sean O’Malley can fight at UFC 248 in March after serving suspension”. ESPN. Retrieved June 9, 2020.
- ^ Needelman J (14 September 2020). “Clemson lineman suspended by ncaa for positive ostarine test opens up for first time”. Retrieved November 13, 2020.
- ^ Bieler D (25 July 2019). “Failed PED test has a highly paid offensive lineman sharing polygraph results”. Washington Post. Retrieved 25 July 2019.
One of the NFL’s highest-paid offensive linemen claimed Wednesday that he did not knowingly take a banned substance he says got him a four-game suspension — and he took a polygraph test in an attempt to prove it.
- ^ “UCI statement on Matteo Spreafico”. Union Cycliste Internationale (UCI). 22 October 2020. Retrieved 2020-10-23.
- ^ “Tandara é suspensa por “potencial violação” do antidoping e está fora das Olimpíadas”.
- ^ “Tokyo Olympics: Team GB 4x100m relay silver medallist CJ Ujah suspended for suspected doping violation”.
- ^ “CJ Ujah: Great Britain lose Tokyo Olympics relay medal after doping violation”. BBC. 18 February 2022.
- ^ “IN THE MATTER OF THE HORSE RACING LICENCE ACT, 2015, S.0.2015,c.38,Sched.9; AND IN THE MATTER OF Robert Gerl” (PDF). Retrieved 2 June 2022.
- ^ “Cardinals WR DeAndre Hopkins still hopes to reduce six-game suspension”. NFL.com. 23 June 2022.
- ^ Saner E (24 April 2018). “Why there are more gym supplements in a London fatberg than cocaine and MDMA”. The Guardian.
//////////GTx-024, MK 2866, Ostarine, enobosarm
O=C(NC1=CC=C(C#N)C(C(F)(F)F)=C1)[C@](C)(O)COC2=CC=C(C#N)C=C2
Betibeglogene autotemcel
Betibeglogene autotemcel
ベチベグロゲンアウトテムセル
2022/8/17, FDA APPROVED Zynteglo
Cellular therapy product
Treatment of betathalassemia
BB305 LVV
bb 1111
BB305 transduced SCD CD34+ HSCs bb1111
LentiGlobin BB305 LVV-transduced autologous SCD CD34+ HSCs bb1111
LentiGlobin drug product for SCD
LentiGlobin drug product for sickle cell disease
LentiGlobin for SCD bb1111
Betibeglogene autotemcel, sold under the brand name Zynteglo, is a medication for the treatment for beta thalassemia.[1][5][2] It was developed by Bluebird Bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in February 2015.[6][7]
The most common adverse reactions include reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch).[5]
It was approved for medical use in the European Union in May 2019,[2] and in the United States in August 2022.[5]
FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions
https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-whoFor Immediate Release:August 17, 2022
Today, the U.S. Food and Drug Administration approved Zynteglo (betibeglogene autotemcel), the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.
“Today’s approval is an important advance in the treatment of beta-thalassemia, particularly in individuals who require ongoing red blood cell transfusions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Given the potential health complications associated with this serious disease, this action highlights the FDA’s continued commitment to supporting development of innovative therapies for patients who have limited treatment options.”
Beta-thalassemia is a type of inherited blood disorder that causes a reduction of normal hemoglobin and red blood cells in the blood, through mutations in the beta-globin subunit, leading to insufficient delivery of oxygen in the body. The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications. Transfusion-dependent beta-thalassemia, the most severe form of the condition, generally requires life-long red blood cell transfusions as the standard course of treatment. These regular transfusions can be associated with multiple health complications of their own, including problems in the heart, liver and other organs due to an excessive build-up of iron in the body.
Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient’s own cells (bone marrow stem cells) that are genetically modified to produce functional beta-globin (a hemoglobin component).
The safety and effectiveness of Zynteglo were established in two multicenter clinical studies that included adult and pediatric patients with beta-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence, which is attained when the patient maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence.
The most common adverse reactions associated with Zynteglo included reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch).
There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in studies of Zynteglo. Patients who receive Zynteglo should have their blood monitored for at least 15 years for any evidence of cancer. Patients should also be monitored for hypersensitivity reactions during Zynteglo administration and should be monitored for thrombocytopenia and bleeding.
This application was granted a rare pediatric disease voucher, in addition to receiving Priority Review, Fast Track, Breakthrough Therapy, and Orphan designations.
The FDA granted approval of Zynteglo to bluebird bio, Inc.
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| Clinical data | |
|---|---|
| Trade names | Zynteglo |
| Other names | LentiGlobin BB305, autologous CD34+ cells encoding βA-T87Q-globin gene |
| License data | EU EMA: by INNUS DailyMed: Betibeglogene autotemcel |
| Pregnancy category | Contraindicated[1][2] |
| Routes of administration | Intravenous[3] |
| ATC code | B06AX02 (WHO) |
| Legal status | |
| Legal status | UK: POM (Prescription only) [1]US: ℞-only [3][4][5]EU: Rx-only [2]In general: ℞ (Prescription only) |
| Identifiers | |
| UNII | MEE8487RTP |
| KEGG | D11930 |
Medical uses
Betibeglogene autotemcel is indicated for the treatment of people twelve years and older with transfusion-dependent beta thalassemia (TDT) who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available.[2]
Betibeglogene autotemcel is made individually for each recipient out of stem cells collected from their blood, and must only be given to the recipient for whom it is made.[2] It is given as an autologous intravenous infusion and the dose depends on the recipient’s body weight.[3][2]
Before betibeglogene autotemcel is given, the recipient receives conditioning chemotherapy to clear their bone marrow of cells (myeloablation).[2]
To make betibeglogene autotemcel, the stem cells taken from the recipient’s blood are modified by a virus that carries working copies of the beta globin gene into the cells.[2] When these modified cells are given back to the recipient, they are transported in the bloodstream to the bone marrow where they start to make healthy red blood cells that produce beta globin.[2] The effects of betibeglogene autotemcel are expected to last for the recipient’s lifetime.[2]
Mechanism of action
Beta thalassemia is caused by mutations to or deletions of the HBB gene leading to reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals.[8] LentiGlobin BB305 is a lentiviral vector which inserts a functioning version of the HBB gene into a recipient’s blood-producing hematopoietic stem cells (HSC) ex vivo. The resulting engineered HSCs are then reintroduced to the recipient.[9][10]
History
In early clinical trials several participants with beta thalassemia, who usually require frequent blood transfusions to treat their disease, were able to forgo blood transfusions for extended periods of time.[11][12][13] In 2018, results from phase 1-2 trials suggested that of 22 participants receiving Lentiglobin gene therapy, 15 were able to stop or reduce regular blood transfusions.[14][15]
In February 2021, a clinical trial[16] of betibeglogene autotemcel in sickle cell anemia was suspended following an unexpected instance of acute myeloid leukemia.[17] The HGB-206 Phase 1/2 study is expected to conclude in March 2023.[16]
It was designated an orphan drug by the European Medicines Agency (EMA) and by the U.S. Food and Drug Administration (FDA) in 2013.[2][18] The Food and Drug Administration has also declared betibeglogene autotemcel a Regenerative Medicine Advanced Therapy.[19]
The safety and effectiveness of betibeglogene autotemcel were established in two multicenter clinical studies that included adult and pediatric particpiants with beta-thalassemia requiring regular transfusions.[5] Effectiveness was established based on achievement of transfusion independence, which is attained when the particpiant maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 particpiants receiving betibeglogene autotemcel, 89% achieved transfusion independence.[5]
Society and culture
Legal status
It was approved for medical use in the European Union in May 2019,[2] and in the United States in August 2022.[5]
Names
The international nonproprietary name (INN) is betibeglogene autotemcel.[20]
References
- ^ Jump up to:a b c “Zynteglo dispersion for infusion – Summary of Product Characteristics (SmPC)”. (emc). 12 May 2020. Retrieved 3 January 2021.[permanent dead link]
- ^ Jump up to:a b c d e f g h i j k l m “Zynteglo EPAR”. European Medicines Agency (EMA). 25 March 2019. Archived from the original on 16 August 2019. Retrieved 16 August 2019. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b c “Archived copy”. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
- ^ “Zynteglo”. U.S. Food and Drug Administration. 17 August 2022. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
- ^ Jump up to:a b c d e f g “FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions”. U.S. Food and Drug Administration (FDA) (Press release). 17 August 2022. Archived from the original on 21 August 2022. Retrieved 20 August 2022. This article incorporates text from this source, which is in the public domain.
- ^ “Ten things you might have missed Monday from the world of business”. The Boston Globe. 3 February 2015. Archived from the original on 1 August 2020. Retrieved 13 February 2015.
- ^ “Lentiviral vectors”. 27 June 2019. Archived from the original on 21 August 2022. Retrieved 8 July 2019.
- ^ Cao A, Galanello R (February 2010). “Beta-thalassemia”. Genetics in Medicine. 12 (2): 61–76. doi:10.1097/GIM.0b013e3181cd68ed. PMID 20098328.
- ^ Negre O, Bartholomae C, Beuzard Y, Cavazzana M, Christiansen L, Courne C, et al. (2015). “Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease” (PDF). Current Gene Therapy. 15 (1): 64–81. doi:10.2174/1566523214666141127095336. PMC 4440358. PMID 25429463. Archived (PDF) from the original on 19 July 2018. Retrieved 19 June 2018.
- ^ Thompson AA, Rasko JE, Hongeng S, Kwiatkowski JL, Schiller G, von Kalle C, et al. (2014). “Initial Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for β-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βΑ-T87Q -Globin Vector (LentiGlobin BB305 Drug Product)”. Blood. 124 (21): 549. doi:10.1182/blood.V124.21.549.549. Archived from the original on 18 October 2019. Retrieved 13 February 2015.
- ^ Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. (September 2010). “Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia”. Nature. 467 (7313): 318–322. Bibcode:2010Natur.467..318C. doi:10.1038/nature09328. PMC 3355472. PMID 20844535.
- ^ Winslow R (8 December 2015). “New Gene Therapy Shows Promise for Lethal Blood Disease”. The Wall Street Journal. Archived from the original on 2 March 2020. Retrieved 13 February 2015.
- ^ (8 December 2014) bluebird bio Announces Data Demonstrating First Four Patients with β-Thalassemia Major Treated with LentiGlobin are Transfusion-Free Archived 26 September 2015 at the Wayback Machine Yahoo News, Retrieved 17 May 2015
- ^ Thompson AA, Walters MC, Kwiatkowski J, Rasko JE, Ribeil JA, Hongeng S, et al. (April 2018). “Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia”. The New England Journal of Medicine. 378 (16): 1479–1493. doi:10.1056/NEJMoa1705342. PMID 29669226.
- ^ Stein R (18 April 2018). “Gene Therapy For Inherited Blood Disorder Reduced Transfusions”. NPR. Archived from the original on 21 August 2022. Retrieved 4 March 2019.
- ^ Jump up to:a b Clinical trial number NCT02140554 for “A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease” at ClinicalTrials.gov
- ^ “Bluebird bio Halts Sickle Cell Trials After Leukemia Diagnosis”. BioSpace. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
- ^ “Autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human BA-T87Q-globin gene Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). 18 March 2013. Archived from the original on 9 June 2020. Retrieved 8 June 2020.
- ^ “bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111)”. Bluebird Bio (Press release). 16 February 2021. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
- ^ World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 34 (1): 34. Archived from the original on 15 July 2020.
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BB305 transduced SCD CD34+ HSCs bb1111
LentiGlobin BB305 LVV-transduced autologous SCD CD34+ HSCs bb1111
LentiGlobin drug product for SCD
LentiGlobin drug product for sickle cell disease
LentiGlobin for SCD bb1111
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