Recently Bristol Myers Squibb and

Recently, Bristol-Myers Squibb and Merck reported their GPR40 agonist research focused on the modification of α,β-position of phenylpropionic APY29 synthesis derivatives. For example, in recent published patent applications, Bristol-Myers Squibb claimed the pyrrolidine and dihydropyrazole GPR40 agonists with high potency. They also tried to improve the polarity through using rigid piperidin-4-ol as linker and replacing the phenyl ring with pyrazine (Fig. 15) [60], [61], [62]. Merck employed similar strategy in the design and discovery of new structure GPR40 agonists. They were interested in the double substitution on α,β-positions to the carboxylic acid. Among the structures claimed in their patent application, the introduction of chiral cyclopropyl and methyl group into α-, and β-position, respectively, conferred potent GPR40 agonistic activity (27, Fig. 16). The conformational constriction in the two positions via cyclization into a tricyclic core also resulted in an increase in the potency and selectivity (28, Fig. 16) [63], [64]. Merck further tried the bioisostere replacement of the carboxylic acid. i.e. thiazolidine-2,4-dione, oxazolidine-2,4-dione to improve the bioavailability with the potency retention (29–30, Fig. 17) [65], [66]. Other bioisosteres of carboxylic acid, such as 3-hydroxyisoxazole, 1,2,4-oxadiazolidine-3,5-dione and (Fig. 17) were tolerant with acceptable potency [67]. In conclusion, GPR40 still remains a viable and promising target for the treatment of T2DM, since the activation of GPR40 undoubtedly improves glycemic control by inducing insulin secretion in a glucose-dependent manner and incretin secretion from intestinal endocrine cells. Compared to GLP-1 analogues and sulfonylureas, GPR40 agonists possess the advantages of being orally bioavailable and improving patient compliance. However, the safety of targeting GPR40 was questioned following the withdrawal of TAK-875 from phase III clinical trials due to concerns about liver toxicity. It is unknown whether the hepatotoxicity was specifically involved in the structure of TAK-875 or in the mechanism of action, but it is clear that full and safe exploitation of GPR40′s therapeutic potential will require a deeper and more detailed understanding of the biology and pharmacology of the target, especially on the receptor’s signaling spectrum activated by endogenous ligand, partial agonist and full agonist. Encouragingly, the recent discloser of allosterism and biased agonism at GPR40 offers many therapeutic possibilities and triggers the new idea to design bitopic ligands of GPR40 to increase the safety and therapeutic efficacy. Furthermore, the cyrstalization of GPR40 bound to TAK-875 will facilitate the structure-based discovery of chemically and structurally diverse GPR40 agonists with better PK and off-target selectivity profiles as well as distinct binding modes, which may potentially circumvent the hepatotoxic effects observed with TAK-875.
Acknowledgements Financial supports from the National Natural Science Foundation of China (81325020) and the “Personalized Medicines—Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040311) were greatly appreciated.
Introduction Free fatty acids (FFAs) are essential dietary nutrients and mediate several biological effects via binding to FFA receptors (FFARs), which belong to a member of G-protein-coupled receptors (GPCRs). GPCR 120 (GPR120) and GPR40 are identified as GPCRs for unsaturated medium- and long-chain (C8-C22) FFAs [1], [2], [3], [4]. GPR120 are highly expressed in gastrointestinal tract, lung, adipocytes and macrophages, while high expression of GPR40 is found in pancreatic beta cells. GPR120 induces hormone secretion from pancreatic tissues and digestive tract and regulates anti-inflammatory responses [1], [5], [6], [7]. On the other hand, the insulin secretion by glucose is stimulated through GPR40 in pancreatic islet cells [4]. Therefore, GPR120 and GPR40 are considered as potent target molecules for the treatment of metabolic diseases, inflammation and cardiovascular disorders [8], [9].