Activation of the glucagon-like peptide-1 (GLP-1) receptor stimulates insulin release, lowers plasma glucose levels, delays gastric emptying, increases satiety, suppresses food intake, and affords weight loss in humans. These beneficial attributes have made peptide-based agonists valuable tools for the treatment of type 2 diabetes mellitus and obesity. However, efficient, and consistent delivery of peptide agents generally requires subcutaneous injection, which can reduce patient utilization. Traditional orally absorbed small molecules for this target may offer improved patient compliance as well as the opportunity for co-formulation with other oral therapeutics. Herein, we describe an SAR investigation leading to small-molecule GLP-1 receptor agonists that represent a series that parallels the recently reported clinical candidate danuglipron. In the event, identification of a benzyloxypyrimidine lead, using a sensitized high-throughput GLP-1 agonist assay, was followed by optimization of the SAR using substituent modifications analogous to those discovered in the danuglipron series. A new series of 6-azaspiro[2.5]octane molecules was optimized into potent GLP-1 agonists. Information gleaned from cryogenic electron microscope structures was used to rationalize the SAR of the optimized compounds.

胰高血糖素样肽-1 (GLP-1) 受体的激活可刺激胰岛素释放、降低血浆葡萄糖水平、延迟胃排空、增加饱腹感、抑制食物摄入并减轻人类体重。这些有益的特性使基于肽的激动剂成为治疗2 型糖尿病和肥胖症的宝贵工具。然而，肽制剂的有效且一致的递送通常需要皮下注射，这会降低患者的利用率。针对这一目标的传统口服吸收小分子可以提高患者的依从性，并有机会与其他口服治疗药物联合配制。在此，我们描述了一项 SAR 研究，该研究导致小分子 GLP-1 受体激动剂的出现，该激动剂代表了一系列与最近报道的临床候选药物 danuglipron 类似的药物。结果，使用敏化高通量 GLP-1 激动剂测定法鉴定了苄氧基嘧啶先导化合物，然后使用与 danuglipron 系列中发现的类似的取代基修饰优化 SAR。一系列新的 6-氮杂螺[2.5]辛烷分子被优化为有效的 GLP-1 激动剂。从低温电子显微镜结构中收集的信息用于合理化优化化合物的比吸收率。