Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based β-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10 mg/kg.

2型糖尿病（T2DM）的特征是血浆葡萄糖水平长期升高。使用小分子拮抗剂通过胰高血糖素受体（GCGR）的拮抗作用抑制胰高血糖素诱导的肝葡萄糖输出是改善糖尿病状态下血糖控制的一种有前途的机制。本工作公开了通过有效的对映选择性合成和结构-活性关系（SAR）的探索和优化，发现了作为有效GCGR拮抗剂的基于吲唑的β-丙氨酸衍生物。此类化合物在多种临床前物种中表现出出色的药代动力学特性。在急性狗胰高血糖素激发试验中，当以10 mg / kg口服给药时，化合物13K显着抑制胰高血糖素介导的血糖升高。