Relaxin H2 is a clinically relevant peptide agonist for relaxin family peptide receptor 1 (RXFP1), but a combination of this hormone’s short plasma half-life and the need for injectable delivery limits its therapeutic potential. We sought to overcome these limitations through the development of a potent small molecule (SM) RXFP1 agonist. Although two large SM HTS campaigns failed in identifying suitable hit series, we uncovered novel chemical space starting from the only known SM RXFP1 agonist series, represented by ML290. Following a design–make–test–analyze strategy based on improving early dose to man ranking, we discovered compound 42 (AZ7976), a highly selective RXFP1 agonist with sub-nanomolar potency. We used AZ7976, its 10 000-fold less potent enantiomer 43 and recombinant relaxin H2 to evaluate in vivo pharmacology and demonstrate that AZ7976-mediated heart rate increase in rats was a result of RXFP1 agonism. As a result, AZ7976 was selected as lead for continued optimization.

中文翻译：

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新型强效选择性松弛素家族肽受体 1 (RXFP1) 激动剂系列的鉴定

松弛素 H2 是一种临床相关的松弛素家族肽受体 1 (RXFP1) 肽激动剂，但该激素血浆半衰期短以及需要注射给药限制了其治疗潜力。我们试图通过开发有效的小分子 (SM) RXFP1 激动剂来克服这些限制。尽管两次大型 SM HTS 活动未能确定合适的热门系列，但我们从唯一已知的 SM RXFP1 激动剂系列（以 ML290 为代表）开始发现了新的化学空间。遵循基于改进早期剂量对人体排名的设计-制造-测试-分析策略，我们发现了化合物42 (AZ7976)，一种具有亚纳摩尔效力的高选择性 RXFP1 激动剂。我们使用 AZ7976、其效力低 10,000 倍的对映体43和重组松弛素 H2 来评估体内药理学，并证明 AZ7976 介导的大鼠心率增加是 RXFP1 激动的结果。因此，AZ7976 被选为继续优化的主导产品。