AMG 837 - CAS 865231-46-5
Catalog number: 865231-46-5
Category: Inhibitor
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AMG 837 sodium salt is a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents. It displayed the expected two-fold increase in potency on GPR4 compared to the racemic compound and its activity crossed over to the rat and mouse forms of GPR40. It is a highly potent stimulator of insulin secretion in MIN6 cells with an EC50 comparable to that seen in the aequorin Ca2+-flux assay. It was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo.
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1.Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives
Trost BM;Masters JT;Taft BR;Lumb JP Chem Sci. 2016 Sep 16;7(9):6217-6231. Epub 2016 Jun 10.
We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors. The utility of the method is demonstrated through the elaboration of the chiral β-alkynyl products into a variety of different molecular scaffolds. Its value in complex molecule synthesis is further validated through a concise, enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.
2.GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus: Benefits and Challenges.
Mohammad S Curr Drug Targets. 2016;17(11):1292-300.
Apart from functioning as an energy source and important structural components of biological membranes, Free Fatty acids (FFAs) play a key role in the regulation of metabolic homeostasis. FFAs activate specific G-protein coupled receptors (GPCRs) in pancreatic β-cells, immune cells adipose, and intestine. GPR40 (also known as FFA receptor 1) is primarily expressed in pancreatic .-cells and is activated by medium-chain and long-chain FFAs. GPR40 has been shown to augment glucose dependent insulin secretion (GDIS) from pancreatic .-cells and is widely studied drug discovery target for the treatment of type 2 diabetes mellitus (T2DM) and other metabolic diseases. Several synthetic agonists of GPR40 augment insulin secretion from pancreatic β- cells and consequently improve glucose tolerance and restore metabolic homeostasis in various rodent models of T2DM. GPR40 agonists TAK-875 and AMG 837 have reached clinical trials and TAK 875 was shown to improve glycemic control in Type 2 diabetic patients. However, phase III clinical trials involving TAK-875 were recently terminated due to signs of liver toxicity in patients. Despite this setback, therapies based on GPR40 agonism provide an attractive alternative in the discovery of new anti-diabetic drugs.
3.Cooperative activation of alkyne and thioamide functionalities; direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides.
Yazaki R;Kumagai N;Shibasaki M Chem Asian J. 2011 Jul 4;6(7):1778-90. doi: 10.1002/asia.201100050. Epub 2011 May 2.
A detailed study of the direct catalytic asymmetric conjugate addition of terminal alkynes to α,β-unsaturated thioamides is described. A soft Lewis acid/hard Brønsted base cooperative catalyst, comprising [Cu(CH(3)CN)(4)]PF(6), bisphosphine ligand, and Li(OC(6)H(4)-p-OMe) simultaneously activated both substrates to compensate for the low reactivity of copper alkynylide. A series of control experiments revealed that the intermediate copper-thioamide enolate functioned as a Brønsted base to generate copper alkynylide from the terminal alkyne, thus driving the catalytic cycle through an efficient proton transfer between substrates. These findings led to the identification of a more convenient catalyst using potassium hexamethyldisilazane (KHMDS) as the Brønsted base, which was particularly effective for the reaction of silylacetylenes. Divergent transformation of the thioamide functionality and a concise enantioselective synthesis of a GPR40 receptor agonist AMG-837 highlighted the synthetic utility of the present catalysis.
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CAS 865231-46-5 AMG 837

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