G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.

中文翻译：

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5-氯-4-（（1-（5-氯嘧啶-2-基）哌啶-4-基）氧基）-1-（2-氟-4-（甲基磺酰基）苯基）吡啶-2（1 H）的发现）（BMS-903452），一种靶向GPR119的抗糖尿病临床候选药物

G蛋白偶联受体119（GPR119）主要在胃肠道的胰腺β细胞和肠内分泌细胞中表达。已经显示，GPR119激动剂通过在胰腺中的直接作用来刺激葡萄糖依赖性胰岛素的释放，并通过在胃肠道中的作用来促进肠降血糖素GLP-1的分泌。这种双重作用机制引起了人们对发现小分子GPR119激动剂作为2型糖尿病潜在新疗法的极大兴趣。在本文中，我们描述了发现和优化含有GPR119激动剂的新型吡啶酮。有效的和选择性的BMS-903452（42）在糖尿病的急性和慢性体内啮齿动物模型中都是有效的。计量42 在对正常健康人的单次递增剂量研究中，显示了剂量依赖性的暴露增加和总GLP-1血浆水平增加的趋势。