Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist from Zydus Cadila

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(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid
str1
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate
 

The compounds of theese type lower blood glucose, regulate peripheral satiety, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) and raises the high-density l ipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular restenosis, diabetes and many other related conditions.

The compounds of are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as arteriosclerotic cardiovascular diseases, stroke, coronary heart diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders. -These compounds  are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non-insulin dependent diabetes mel litus (N I DDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabol ism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, l ike arteriosclerosis, atherosclerosis; diabetic retinopathy, diabetic neuropathy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.

Diabetes mellitus is a serious disease affl icting over 1 00 mi l lion people worldwide. In the United States, there are more than 12 mill ion diabetics, with 600,000 new cases diagnosed each year.

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. There are many- types of diabetes, but the two most common are Type 1 (also referred to as insulin- dependent diabetes mellitus or IDDM) and Type II (also referred to as non- insulin-dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same; however, everyone with diabetes has two things in common: overproduction of glucose by the liver and little or no ability to move glucose out of the blood, into the cells where it becomes the body’s primary fuel.

People who do not have diabetes rely on insulin, a hormone made in the pancreas, to move glucose from the blood into the cells of the body. However, people who have diabetes either don’t produce insulin or can’t efficiently use the insulin they produce; therefore, they can’t move glucose into their cells. Glucose accumulates in the blood creating a condition called hyperglycemia, and over time, can cause serious health problems.

Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic syndrome, generally characterized by hyperglycemia, comprises alterations in carbohydrate, fat and protein metabolism caused by absent or markedly reduced insulin secretion and/or ineffective insulin action. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormal ities in the peripheral and autonomic nervous systems are also part of the diabetic syndrome.

About 5% to 10% of the people who have diabetes have IDDM. These individuals don’t produce insulin and therefore must inject insulin to keep their blood glucose levels normal . IDDM is characterized by low or undetectable levels of endogenous insulin production caused by destruction of the insulin-producing β cells of the pancreas, the characteristic that most readily distinguishes IDDM from NIDDM. IDDM, once termed juvenile-onset diabetes, strikes young and older adults alike.

Approximately 90 to 95% of people with diabetes have Type II (or NIDDM). NIDDM subjects produce insulin, but the cells in their bodies are insulin resistant: the cells don’t respond properly to the hormone, so glucose accumulates i n their blood. NIDDM is characterized by a relative disparity between endogenous insulin production and insulin requirements, leading to elevated blood glucose levels. In contrast to IDDM, there is always some endogenous insulin production in NIDDM; many NIDDM patients have normal or even elevated blood insul in levels, whi le other NIDDM patients have inadequate insul in production ( otwein, R. et al. N. Engl. J. Med. 308, 65-71 ( 1983)). Most people diagnosed with NIDDM are age 30 or older, and half of all new cases are age 55 and older. Compared with whites and Asians, NIDDM is more common among Native Americans, African-Americans, Latinos, and Hispanics. In addition, the onset can be insidious or even clinically non-apparent, making diagnosis difficult.

The primary pathogenic lesion on NIDDM has remained elusive. Many have suggested that primary insulin resistance of the peripheral tissues is the initial event. Genetic epidemiological studies have supported this view. Similarly, insulin secretion abnormalities have been argued as the primary defect in NIDDM. It is l ikely that both phenomena are important contributors to the disease process (Rimoin, D. L., et. al. Emery and Rimoin’s Principles and Practice of Medical Genetics 3rd Ed. 1 : 1401 – 1402 ( 1996)).

Many people with NIDDM have sedentary lifestyles and are obese; they weigh approximately 20% more than the recommended weight for their height and build. Furthermore, obesity is characterized by hyperinsul inemia and insul in resistance, a feature shared with NIDDM, hypertension and atherosclerosis.

The G-protein -coupled receptor GPR 40 functions as a receptor for long-chain free fatty acids (FFAs) in the body and as such is impl icated in a large number of metabolic conditions in the body. For example it has been alleged that a GPR 40 agonist promotes insulin secretion whilst a GPR 40 antagonist inhibits insulin secretion and so depending upon the circumstances the agonist and antagonist may be useful as therapeutic agents for the number of insul in related conditions such as type 2 diabetes, obesity, impaired glucose tolerance, insul in resistance, neurodegenerative diseases and the like.

There is increasing evidences that lipids can also serve as extracel lular l igands for a specific class of receptors and thus act as “nutritional sensors” (Nolan CJ et al. J. Clinic. Invest., 2006, 1 1 6, 1 802- 1 812The free fatty acids can regulate cell function. Free fatty acids have demonstrated as ligands for orphan G protein-coupled receptors (GPCRs) and have been proposed to play a critical role in physiological glucose homeostasis.

GPR40, GPR 120, GPR41 and GPR43 exemplify a growing number of GPCRs that have been shown to be activated by free fatty acids. GPR40 and GPR 120 are activated by medium to long-chain free fatty acids whereas GPR 41 and GPR 43 are activated by short-chain fatty acid (Brown AJ et al, 2003).

GPR 40 is highly expressed on pancreatic β-cells, and enhances glucose- stimulated insulin secretion {Nature, 2003, 422, 1 73- 1 76, J. Bio. Chem. 2003, 278, 1 1303- 1 13 1 1 , Biochem. Biophys. Res. Commun. 2003, 301, 406-4 10).

Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 is reported {Lett, to Nature 2003, 422, 1 73- 1 76).

GlaxoSmith line Research and Development, US published an article in Bioorg. Med. Chem. Lett. 2006, 16, 1840- 1 845 titled Synthesis and activity of small molecule GPR40 agonists. (Does this describe GW9508?)Another article titled Pharmacological regulation of insul in secretion in ΜΓΝ6 cells through the fatty – acid receptor GPR40: Identification of agonist and antagonist small molecules is reported in

Br. J. Pharmacol. 2006, 148, 619-928 from GlaxoSmithKl i ne. USA (Does this describe GW9508?) ‘

GW 9508.

Solid phase synthesis and SAR of small molecule agonists for the. GPR 40 receptor is published in Bioorg. Med. Chem. Lett. 2007, 16, 1 840- 1 845 by Glaxo Smith line Res. 8c Dev. USA, including those with the following structures.

Johnson & Johnson Pharmaceutical Research and development , USA published

Synthesis and Biological Evaluation of 3-Aryl-3-(4-phenoxy)-propanoic acid as a Novel Series of G-protein -coupled receptor 40 agonists J. Med. Chem. 2007,

76, 2807-2817)

National Institutes of Health, Bethesda, Maryland publ ished “Bidirectional Iterative Approach to the Structural Delineation of the Functional Chemo print in GPR 40 for agonist Recognition (J. Med. Chem. 2007. 50, 298 1 -2990).

Discov roglucinols of the following formula

as a new class of GPR40 (FFAR 1 ) agonists has been publ ished by Piramal Li fe Sciences, Ltd. in Bioorg. Med. Chem. Lett. 2008, 1 8, 6357-6361

Synthesis and SAR of 1 ,2,3,4-tctrahydroisoquinoline- l -ones as novel G-protein coupled receptor40(GPR40) antagonists of the following formula has been published in Bioorg. Med. Chem. Lett. 2009, 79, 2400-2403 by Pfizer

Piramal Life Sciences Ltd. published “Progress in the discovery and development of small molecule modulators of G-protei n coupled receptor 40(GPR40/FFA 1 /FFAR1 ), an emerging target for type 2 diabetes” in Exp. Opin. Therapeutic Patents 2009, 19(2), 237 -264.

There was a report published in Zhonggno Bingli Shengli ^Zazhi 2009, 25(7), 1376- 1380 from Sun Yat. Sen University, Guangzhou, which mentions the role GPR 40 on lipoapoptosis.

A novel class of antagonists for the FFA’s receptor GPR 40 was published in Biochem. Biophy. Res. Commun. 2009 390, 557-563.

N41 (DC260126)

Merck Res. Laboratories published “Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists” having the following formula in Bioorg. Med. Chem. Lett. 2010 20, 1298- 1 301

Discovery of TA -875, a potent, selective, and oral ly bioavai lable G PR 40 agonist is reported by Takeda Pharmaceutical Ltd. ACS Med. Chem. Lett. 2010,

7(6), 290-294

In another report from University of Southern Denmark” Structure -Activity of Dihydrocinnamic acids and discovery of potent FFA l (GPR40) agonist TUG-469″ is reported in ACS Me -349.

The free fatty acid 1 receptor (FFAR 1 or GPR40), which is highly expressed on pancreatic β-cells and amplifies glucose-stimulated insul in secretion, has emerged as an attractive target for the treatment of type 2 diabetes (ACS Med. Chem. Lett. 2010, 1 (6), 290-294).

G-protein coupled receptor (GPR40) expression and its regulation in human pancreatic islets: The role of type 2 diabetes and fatty acids is reported in Nutrition Metabolism & Cardiovascular diseases 2010, 2(9( 1 ), 22-25

Ranbaxy reported “Identification of Berberine as a novel agonist of fatty acid receptor GPR40” in Phytother Res. 2010, 24, 1260-63.

The following substituted 3-(4-aryloxyaryI)-propanoic acids as GPR40 agonists are reported by Merck Res. Lab. in Bioorg. ed. Chem. Lett. 201 1 , 21, 3390-3394

4 EC50=0.970 μΜ 5. EC50=2.484 μΜ

CoMSIA study on substituted aryl alkanoic acid analogs as GPR 40 agonists is reported Chem. Bio. Drug. Des. 201 1 , 77, 361 -372

Takeda further published “Design, Synthesis and biological activity of potential and orally available G-protein coupled receptor 40 agonists” in J. Med. Chem. 201 1 , 54(5), 1365- 1 378.

Amgen disclosed a potent oral ly bioavai lable GPR 40 agonist AMG-837 in Bioorg. Med. Chem. Lett.

Discovery of phenylpropanoic acid derivatives containing polar functional ities as Potent and orally bioavailable G protein-coupled receptor 40 Agonist for the treatment of type 2 Diabetes is reported in J. Med. Chem. 2012, 55, 3756-3776 by Takeda.

Discovery of AM- 1638: A potent and orally bioavailable GPR40/FFA 1 full agonist is reported in ACS Med. Chem. Lett. 2012, 3(9), 726-730.

Ranjit Desai

Ranjit Desai

Sr Vice President. Head-Chemistry
Zydus Research Centre, Ahmedabad · Chemistry

Sameer Agarwal

Sameer Agarwal

Cadila Healthcare Ltd., India

Sameer Agarwal has obtained Master’s in Chemistry from IIT, Delhi and was awarded DAAD (German Govt. Scholarship) fellowship to purse research project at Karlsruhe University, Germany. He has received PhD degree from Technical University, Dresden, Germany in the field of Synthetic and bio-organic chemistry under direction of Prof. Dr. Hans-Joachim Knölker, FRSC, a well-known scientist of present times for his contribution towards Alkaloid Chemistry. He worked as Research Scientist (Post-Doc), JADO Technologies, (collaboration with Max Planck Institute (MPI) of Molecular Cell Biology and Genetics and Chemsitry Department, Technical University), Germany. He then decided to return to his home country and working with Zydus Research Centre, Cadila Healthcare Ltd., Ahmedabad as Principal Scientist / Group Leader in the area of basic drug discovery and his research interest includes discovery of cardio metabolic, anti-inflammatory and oncology drugs. He has large number of publications in international journals and patents and is a reviewer of many prestigious journals including American Chemical Society.

Paper

Identification of an Orally Efficacious GPR40/ FFAR1 Receptor Agonist

ArticleinACS Medicinal Chemistry Letters · September 2016
DOI: 10.1021/acsmedchemlett.6b00331
Abstract Image

GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic β-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound 5, which is highly potent in in vitro assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED50 = 0.8 mg/kg; ED90 = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity

Synthesis of compound 5 is depicted in Scheme 1a.

The reductive amination1 of commercially available 3-thiophene-aldehyde (3) and isopropyl amine using sodium triacetoxyborohydride resulted in secondary amine intermediate 4. Compound 4 on further reductive amination under similar conditions with aldehyde intermediate, (S)-3-(4-((3-formylbenzyl)oxy)phenyl)hex-4-ynoic acid (8), afforded 2d in high yields. The aldehyde intermediate, 8 was obtained from (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (6) as shown in Scheme 1b. Acid 6 was synthesized via 5-step reported procedure using commercially available 4-hydroxybenzaldehyde and Meldrum’s acid.2 Resolution of racemic acid 6 was accomplished via diastereomeric salt formation with (1S,2R)-1-amino-2-indanol followed by salt break with aqueous acid to furnish compound 6. Treatment of 6 with of 40% aqueous tetrabutylphosphonium hydroxide (nBu4POH) in THF, followed by addition of 3-formyl benzyl bromide (7), afforded aldehyde intermediate 8. Compound 2d was further converted to its corresponding calcium salt (5) in two-step sequence with excellent chemical purity.

Scheme 1a. Synthesis of Compounds 2d and 5. Reagent and Conditions: (a) CH(CH3)2NH2, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (b) Comp 8, NaB(OAc)3H, CH3COOH, dry THF, 0 ᵒC to r.t., 16 h; (c) NaOH, MeCN/H2O, r.t., 3 h; (d) CaCl2, MeOH/H2O, r.t., 16 h.

BASE

(S)-3-(4-((3-((isopropyl(thiophen-3- ylmethyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoic acid (1.557 g, 3.34 mmol, 43.0 % yield) as wax solid.

1H NMR (400 MHz, DMSO-d6): δ = 12.35 (br s, 1H), 7.44 (q, J = 3.2 Hz, 2H), 7.32 – 7.24 (m, 6H), 7.04 (d, J = 4.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.06 (s, 2H), 3.93 (d, J = 2.4 Hz, 1H), 3.51 (d, J = 8.8 Hz, 4H), 2.84 (sept, J = 6.4 Hz, 1H), 2.57 (d, J = 8 Hz, 2H), 1.77 (d, J = 2.4 Hz, 3H), 1.01 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT: DMSO-d6, 100MHz):- δ = 172.35 (C), 157.63 (C), 142.13 (C), 141.44 (C), 137.42 (C), 133.93 (C), 128.73 (CH), 128.64 (CH), 128.43 (CH), 127.99 (CH), 127.73 (CH), 126.28 (CH), 122.21 (CH), 115.10 (CH), 81.16 (C), 78.52 (C), 69.69 (CH2), 52.90 (CH2), 48.64 (CH), 48.49 (CH2), 43.44 (CH2), 33.15 (CH), 17.92 (CH3), 3.66 (CH3);

MS (EI): m/z (%) = 462.35 (100) (M+H) + ;

IR (KBr): ν = 3433, 2960, 2918, 2810, 1712, 1608, 1510, 1383, 1240, 1174, 1109, 1018 cm-1 .

CA SALT

calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate (1.51 g, 1.536 mmol, 46% yield) as white powder. mp: 124.5 o C;

1H NMR (400 MHz, DMSO-d6): δ = 7.43 – 7.42 (m, 2H), 7.28 – 7.24 (m, 6H), 7.04 (d, J = 4.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 5.02 (s, 2H), 4.02 (s, 1H), 3.50 (d, J = 7.2 Hz, 4H), 2.84 – 2.77 (sept, J = 6.4 Hz, 1H), 2.43 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 2.28 (dd, J1 = 6.8 Hz, J2 = 7.2 Hz, 1H), 1.73 (s, 3H), 0.99 (d, J = 6.4 Hz, 6H);

13C NMR and DEPT (100 MHz, DMSO-d6): δ = 177.78 (C), 157.23 (C), 142.11 (C), 141.4 (C), 137.46 (C), 135.81 (C), 128.83 (CH), 128.62 (CH), 128.40 (CH), 127.94 (CH), 127.69 (CH), 126.26 (CH), 122.18 (CH), 114.77 (CH), 83.18 (C), 77.32 (C), 69.66 (CH2), 52.89 (CH2), 48.59 (CH), 48.48 (CH2), 46.86 (CH2), 33.52 (CH), 17.88 (CH3), 3.78 (CH3);

MS (EI): m/z (%) = 462.05 (100) (M+H)+ ;

ESI-Q-TOF-MS: m/z [M+H]+ calcd for [C28H31NO3S + H]+ : 462.6280; found: 462.4988;

IR (KBr): ν = 3435, 2960, 2918, 2868, 2818, 1608, 1550, 1508, 1440, 1383, 1359, 1240 cm-1 ;

HPLC (% Purity) = 99.38%; Calcium Content (C56H60CaN2O6S2) Calcd.: 4.17%. Found: 3.99%.

 COMPD Ca salt

Calcium (S)-3-(4-((3-((isopropyl(thiophen-3-yl methyl)amino)methyl)benzyl)oxy)phenyl)hex-4-ynoate

 

 

 

Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist

Zydus Research Centre, Cadila Healthcare Ltd., Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad-382 210, India
ACS Med. Chem. Lett., Article ASAP
DOI: 10.1021/acsmedchemlett.6b00331
*(S.A.) E-mail: sameeragarwal@zyduscadila.com or sameer_ag@yahoo.com., *(R.C.D.) E-mail: ranjitdesai@zyduscadila.com. Fax:+91-2717-665355. Tel: +91-2717-665555.
Ranjit Desai

Sr Vice President, Head Chemistry

Zydus Cadila

– Present (4 years)Zydus Research Centre, Ahmedabad, India

Pankaj Patel, chairman and MD, Cadila Healthcare Ltd

 Dr. Mukul Jain

Senior Vice President at Zydus Research Centre

Prashant Deshmukh

Prashant Deshmukh

Research Officer at Zydus Cadila

Dr. Poonam Giri

Dr. Poonam Giri

Principal Scientist at Zydus Research Centre

Bhadresh Rami

Bhadresh Rami

Debdutta Bandyopadhyay

Debdutta Bandyopadhyay

Senior General manager at Zydus Research Centre

Suresh Giri

Suresh Giri

Research Scientist

References
1. Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures. J. Org. Chem., 1996, 61 (11), 3849–3862.
2. Walker, S. D.; Borths, C. J.; DiVirgilio, E.; Huang, L.; Liu, P.; Morrison, H.; Sugi, K.; Tanaka, M.; Woo, J. C. S.; Faul, M. M. Development of a Scalable Synthesis of a GPR40 Receptor Agonist. Org. Process Res. Dev. 2011, 15, 570–580.
3. Desai, R. C., Agarwal, S. Novel Heterocyclic Compounds, Pharmaceutical Compositions and Uses Thereof. Indian Pat. Appl. 2025/MUM/2015, 25 May 2015.
4. Cheng, Z., Garvin, D., Paguio, A., Stecha, P., Wood, K., & Fan, F. Luciferase Reporter Assay System for Deciphering GPCR Pathways. Current Chemical Genomics, 2010, 4, 84–91. http://doi.org/10.2174/1875397301004010084
5. Arkin, M. R., Connor, P. R., Emkey, R., et al. FLIPR™ Assays for GPCR and Ion Channel Targets. 2012 May 1 [Updated 2012 Oct 1]. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92012/
6. Garbison, K. E., Heinz, B. A., Lajiness, M. E. IP-3/IP-1 Assays. 2012 May 1. In: Sittampalam, G. S., Coussens, N. P., Nelson, H., et al., editors. Assay Guidance Manual [Internet]. Bethesda (MD): Eli Lilly & Company and the National Center for Advancing Translational Sciences; 2004. Available from: http://www.ncbi.nlm.nih.gov/books/NBK92004/
7. Milić, A., Mihaljević, V.B., Ralić, J. et al. A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents. Eur J Drug Metab Pharmacokinet, 2014, 39, 263. doi:10.1007/s13318-013-0155-8
8. Bell, R. H.; Hye, R. J. Animal models of diabetes mellitus: physiology and pathology. J. Surg. Res. 1983, 35, 433-460.
9. Shafrir, E. Animal models of non insulin dependent diabetes. Diabetes Metab Rev. 1992, 8, 179- 208.
PATENT
PAPER

Development of a Scalable Synthesis of a GPR40 Receptor Agonist

Chemical Process Research and Development, Amgen Inc., Thousand Oaks, California 91320, United States
Org. Process Res. Dev., 2011, 15 (3), pp 570–580
*Tel: 805-313-5152. Fax: 805-375-4532. E-mail: walkers@amgen.com.
Abstract Image

Early process development and salt selection for AMG 837, a novel GPR40 receptor agonist, is described. The synthetic route to AMG 837 involved the convergent synthesis and coupling of two key fragments, (S)-3-(4-hydroxyphenyl)hex-4-ynoic acid (1) and 3-(bromomethyl)-4′-(trifluoromethyl)biphenyl (2). The chiral β-alkynyl acid 1 was prepared in 35% overall yield via classical resolution of the corresponding racemic acid (±)-1. An efficient and scalable synthesis of (±)-1 was achieved via a telescoped sequence of reactions including the conjugate alkynylation of an in situ protected Meldrum’s acid derived acceptor prepared from 3. The biaryl bromide 2 was prepared in 86% yield via a 2-step Suzuki−Miyaura coupling−bromination sequence. Chemoselective phenol alkylation mediated by tetrabutylphosphonium hydroxide allowed direct coupling of 1 and 2 to afford AMG 837. Due to the poor physiochemical stability of the free acid form of the drug substance, a sodium salt form was selected for early development, and a more stable, crystalline hemicalcium salt dihydrate form was subsequently developed. Overall, the original 12-step synthesis of AMG 837 was replaced by a robust 9-step route affording the target in 25% yield.

 Image result for AMG 837
CAS [1291087-14-3] AMG 837
 Image result for AMG 837
“Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide”
Yazaki, R.; Kumagai, N.; Shibasaki, M.
Org. Lett. 2011, 13, 952.   highlighted by Synfacts 2011, 6, 586.
NMR

 

 

/////////fatty acids, FFAR1 GPR40, GPR40 agonist, insulin secretion, type 2 diabetes, GPR40/FFAR1 Receptor Agonist, ZYDUS CADILA
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O[Ca]OC(C[C@@H](c4ccc(cc4)OCc5cc(ccc5)CN(Cc6ccsc6)C(C)C)C#CC)=O)C#CC
c1(ccc(cc1)OCc2cc(ccc2)CN(Cc3ccsc3)C(C)C)[C@H](CC(=O)O)C#CC
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