Optimization of the highly potent and selective, yet metabolically unstable and poorly soluble hRXFP1 agonist AZ7976 led to the identification of the clinical candidate, AZD5462. Assessment of RXFP1-dependent cell signaling demonstrated that AZD5462 activates a highly similar panel of downstream pathways as relaxin H2 but does not modulate relaxin H2-mediated cAMP second messenger responsiveness. The therapeutic potential of AZD5462 was assessed in a translatable cynomolgus monkey heart failure model. Following 8 weeks of treatment with AZD5462, robust improvements in functional cardiac parameters including LVEF were observed at weeks 9, 13, and 17 without changes in heart rate or mean arterial blood pressure. AZD5462 was well tolerated in both rat and cynomolgus monkey and has successfully completed phase I studies in healthy volunteers. In summary, AZD5462 is a small molecule pharmacological mimetic of relaxin H2 signaling at RXFP1 and holds promise as a potential therapeutic approach to treat heart failure patients.

中文翻译：

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发现临床候选药物 AZD5462，一种用于治疗心力衰竭的选择性口服变构 RXFP1 激动剂

对高效、选择性但代谢不稳定且难溶性 hRXFP1 激动剂 AZ7976 进行优化，最终确定了临床候选药物 AZD5462。对 RXFP1 依赖性细胞信号传导的评估表明，AZD5462 激活一组与松弛素 H2 高度相似的下游通路，但不调节松弛素 H2 介导的 cAMP 第二信使反应性。在可转化的食蟹猴心力衰竭模型中评估了 AZD5462 的治疗潜力。使用 AZD5462 治疗 8 周后，在第 9、13 和 17 周观察到包括 LVEF 在内的功能性心脏参数的强劲改善，且心率或平均动脉血压没有变化。 AZD5462 在大鼠和食蟹猴中均具有良好的耐受性，并已在健康志愿者中成功完成了 I 期研究。总之，AZD5462 是 RXFP1 松弛素 H2 信号传导的小分子药理学模拟物，有望成为治疗心力衰竭患者的潜在治疗方法。