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Home » Preclinical drugs » BMS-986118, for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)

BMS-986118, for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)

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BMS-986118
BMS compd for treatment for type 2 diabetes( GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion)
Cas 1610562-74-7
1H-Pyrazole-5-acetic acid, 1-[4-[[(3R,4R)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)-
Molecular Weight, 540.96, C25 H28 Cl F3 N4 O4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid

(-)-[(4S,5S)-1-(4-[[(3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid

  • (4S,5S)-1-[4-[[(3R,4R)-1-(5-Chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-1H-pyrazole-5-acetic acid
  • 2-[(4S,5S)-1-[4-[[1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl]oxy]phenyl]-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl]acetic acid isomer 2

BMS-986118 is a GPR40 full agonist. GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia

Image result for bms

NOTE CAS OF , 1H-Pyrazole-5-acetic acid, 1-[4-[[(3S,4S)-1-(5-chloro-2-methoxy-4-pyridinyl)-3-methyl-4-piperidinyl]oxy]phenyl]-4,5-dihydro-4-methyl-3-(trifluoromethyl)-, (4S,5S)- IS 1610562-73-6

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Image result for BMS-986118,

SYNTHESIS

WO 2014078610

PAPER

https://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00982

Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists

Abstract

Abstract Image

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitroIn vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

Compound 4

2-((4S,5S)-1-(4-(((3R,4R)-1-(5-Chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (4)

To a stirred solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (5.5 g, 9.9 mmol) in THF (90 mL) and water (9 mL) at room temperature was added 2 N LiOH solution (12 mL, 24 mmol). The reaction mixture was stirred at room temperature for 16 h, and 1 N HCl (25 mL, 25 mmol) was added at 0 °C to pH = 4–5. The solvent was evaporated, and the residue was extracted three times with EtOAc. The organic extracts were dried over Na2SO4; the solution was filtered and concentrated. The residue was recrystallized from isopropanol to give 4(neutral form) as white solid (4.3 g, 7.7 mmol, 78% yield).
1H NMR (500 MHz, DMSO-d6) δ ppm 12.52 (br s, 1H), 8.01 (s, 1H), 7.05 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 2H), 6.40 (s, 1H), 4.49–4.33 (m, 1H), 4.02 (td, J = 8.8, 4.1 Hz, 1H), 3.80 (s, 3H), 3.56–3.39 (m, 2H), 3.37–3.29 (m, 1H), 2.94–2.85 (m, 1H), 2.72–2.66 (m, 1H), 2.64 (dd, J = 16.1, 2.9 Hz, 1H), 2.49–2.41 (m, 1H), 2.22–2.05 (m, 1H), 2.01–1.86 (m, 1H), 1.68–1.50 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H).
 
13C NMR (126 MHz, DMSO-d6) δ 171.5, 163.7, 157.1, 152.5, 146.3, 139.7 (q, J = 34.7 Hz), 136.2, 121.7 (q, J = 269.3 Hz), 117.3, 117.2, 116.0, 100.4, 78.9, 65.6, 54.2, 53.4, 47.8, 44.2, 36.0, 34.9, 29.5, 17.4, 15.3. 19F NMR (471 MHz, DMSO-d6) δ −61.94 (s, 3F).
 
Optical rotation: [α]D(20)−11.44 (c 2.01, MeOH).
 
HRMS (ESI/HESI) m/z: [M + H]+ Calcd for C25H29ClF3N4O4 541.1824; Found 541.1813. HPLC (Orthogonal method, 30% Solvent B start): RT = 11.9 min, HI: 97%. m/zobs 541.0 [M + H]+.
 
Melting point = 185.5 °C.
PAPER

Palladium-Catalyzed C–O Coupling of a Sterically Hindered Secondary Alcohol with an Aryl Bromide and Significant Purity Upgrade in the API Step

Chemical and Synthetic DevelopmentBristol-Myers Squibb CompanyOne Squibb Drive, New Brunswick, New Jersey08903, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.8b00022

Abstract

Abstract Image

The final two steps used to prepare greater than 1 kg of a compound evaluated as a treatment for type 2 diabetes are reported. The application of a palladium-catalyzed C–O coupling presented significant challenges due to the nature of the reactants, impurities produced, and noncrystalline coupling intermediate. Process development was able to address these limitations and enable production of kilogram quantities of the active pharmaceutical ingredient (API) in greater efficiency than a Mitsunobu reaction for formation of the key bond. The development of a sequence that telescopes the coupling with the subsequent ester hydrolysis to yield the API and the workup and final product crystallization necessary to produce high-quality drug substance without the need of column chromatography are discussed.

Bruce Ellsworth

Bruce Ellsworth, Director, Head of Fibrosis Discovery Chemistry at Bristol-Myers Squibb

Rick EwingRick Ewing, Head, External Partnerships, Discovery Chemistry and Molecular Technologies at Bristol-Myers Squibb
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PATENT
WO 2014078610
Original Assignee Bristol-Myers Squibb Company
Patent
Patent ID

Patent Title

Submitted Date

Granted Date

US9133163 DIHYDROPYRAZOLE GPR40 MODULATORS
2013-11-15
2014-05-22
US9604964 Dihydropyrazole GPR40 modulators
2013-11-15
2017-03-28
REF
1: Li Z, Qiu Q, Geng X, Yang J, Huang W, Qian H. Free fatty acid receptor
agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II
clinical development. Expert Opin Investig Drugs. 2016 Aug;25(8):871-90. doi:
10.1080/13543784.2016.1189530. PubMed PMID: 27171154.
2
Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
248th Am Chem Soc (ACS) Natl Meet (August 10-14, San Francisco) 2014, Abst MEDI 31
MEDI John Macor Sunday, August 10, 2014
Oral Session
General Oral Session – PM Session
Organizers: John Macor
Presiders: John Macor
Duration: 1:30 pm – 5:15 pm
1:55 pm 31 Discovery of BMS-986118, a dual MOA GPR40 agonist that produces glucose-dependent insulin and GLP-1 secretion
Bruce A Ellsworth, Jun Shi, Elizabeth A Jurica, Laura L Nielsen, Ximao Wu, Andres H Hernandez, Zhenghua Wang, Zhengxiang Gu, Kristin N Williams, Bin Chen, Emily C Cherney, Xiang-Yang Ye, Ying Wang, Min Zhou, Gary Cao, Chunshan Xie, Jason J Wilkes, Heng Liu, Lori K Kunselman, Arun Kumar Gupta, Ramya Jayarama, Thangeswaran Ramar, J. Prasada Rao, Bradley A Zinker, Qin Sun, Elizabeth A Dierks, Kimberly A Foster, Tao Wang, Mary Ellen Cvijic, Jean M Whaley, Jeffrey A Robl, William R Ewing.

///////////BMS-986118, Preclinical, BMS, Bruce A. Ellsworth,  Jun Shi,  William R. Ewing,  Elizabeth A. Jurica,  Andres S. Hernandez,  Ximao Wu, DIABETES,

COc1cc(c(Cl)cn1)N4CCC(Oc2ccc(cc2)N3N=C([C@@H](C)C3CC(=O)O)C(F)(F)F)[C@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@@H](C)C4

COc1cc(c(Cl)cn1)N4CC[C@@H](Oc2ccc(cc2)N3N=C([C@@H](C)[C@@H]3CC(=O)O)C(F)(F)F)[C@H](C)C4

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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