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  • Pam3CSK4 synthesis br Results and discussion br Conclusion I

    2021-11-26


    Results and discussion
    Conclusion In summary, we designed and discovered a series of novel GPR40 agonists containing 3,5-dimethylisoxazole with improved tPSA and ideal cLog P. Most of these compounds were confirmed as excellent GPR40 agonists in vitro. Especially, compound 11k exhibited robust potency of glycemic control in both ICR mice and type 2 diabetic C57BL/6 mice compared with TAK-875. The pharmacokinetic profiles was evaluated and presented desirable results. In addition, docking studies were conducted to explain the potency of 3,5-dimethylisoxazole analogues. Those qualities made compound 11k a promising lead compound for the treatment of T2DM and worth for further investigation.
    Experimental section
    Acknowledgments This study was supported by the Natural Science Foundation of Jiangsu Province (No. BK 20141349) and the China National Key HiTech Innovation Project for the R&D of Novel Drugs (No. 2013ZX09301303-002).
    GPR40 (also known as FFA1) is a free fatty acid-activated Gq-coupled class 1 GPCR that is found on the surfaces of pancreatic β-cells, gastrointestinal enteroendocrine cells, immune cells and also parts of the brain. Medium- (C6–C12) and long chain (C14–C24) saturated and unsaturated fatty acids stimulate GPR40, and evidence points to GPR40 being a mechanistic link to the well-known effects of fatty acids to acutely stimulate insulin and incretin secretion., , The effect of fatty Pam3CSK4 synthesis on insulin and incretin (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) secretion is blunted or eliminated in mice lacking GPR40. GPR40 knockout mice also show impaired glucose and arginine induced insulin secretion in vivo. Based on these studies, GPR40 may serve as an attractive target to mediate insulin secretion and agents that serve as GPR40 agonists may be useful for the treatment of type-2 diabetes. Because activity of GPR40 agonists on islet β-cells is glucose dependent, it is believed that GPR40 may offer advantages to commonly used sulfonylurea drugs which act independently of ambient glucose levels, resulting in hypoglycemia in some patients. Potent small molecule GPR40 agonists based on scaffolds such as aryalkanoic acids and thiazolidinediones have been reported by several groups. More recently, research in Takeda Pharmaceutical Co. Ltd led to discovery of TAK-875 (), a potent and orally bioavailable small molecule GPR40 agonist, which is currently undergoing phase III human clinical trials. This Letter describes the design, synthesis and biological activity of a series of novel orally bioavailable small molecular GPR40 agonists with improved potency and physiochemical properties. Based on a published docking study, of TAK-875 in a GPR40 homology model, the middle phenyl ring is orthogonal to the right dihydrobenzofuran ring as well as the left 2,6-dimethylphenyl ring, this conformation allowed this molecule to fit into the active pocket of GPR40 with multiple hydrophilic as well as hydrophobic interactions. To design a novel series of GPR40 agonist, we tried to introduce conformational restrictions into the TAK-875 skeleton, which may result in decreased molecular flexibility and less rotatable bonds, and in this way improve the physiochemical properties while preserving GPR40 agonistic potency. Based on the predicted binding conformation of TAK-875,, introduction of a fused dioxane ring into TAK-875 provided a pair of two diastereoisomers , (a). Comparison of the energy minimized conformation of and TAK-875 resulted in high percentage of overlap, indicating good chance of being a potent GPR40 agonist (b). We then set up to synthesis compounds , and tested them as GPR40 agonists. Synthesis of was outlined in . Compounds and were synthesized via published procedures. Wittig reaction of , followed by Sharpless asymmetric di-hydroxylation with AD-mix α and selective TBS protection of the primary alcohol led to intermediate . Iodination of compound with equimolar ICl gave intermediate , which was coupled with under typical Mitsnobu conditions, followed by TBAF deprotection, giving intermediate . Palladium catalyzed intra-molecular cyclization of , followed by sodium hydroxide hydrolysis giving the final product . Compound is a diastereomer of and is synthesized via similar procedures except using AD-mix βas chiral reagent in step ii.