Pharmaceuticals, Research and Development, Bayer AG, Aprather Weg 18a, 42113 Wuppertal, Germany.
University of Witten/Herdecke, 58455 Witten, Germany.
J Med Chem. 2023 Jun 8;66(11):7280-7303. doi: 10.1021/acs.jmedchem.2c02082. Epub 2023 Apr 11.
Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators and . It turned out that BAY 1165747 (BAY-747, ) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 () demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.
在此，我们描述了新型可溶性鸟苷酸环化酶（sGC）刺激剂的鉴定、化学优化和临床前特征。鉴于 sGC 刺激剂具有广泛的治疗机会，未来将需要针对不同适应症、具有特定药代动力学、组织分布和理化性质的新型定制分子。在这里，我们报告了基于超高通量（uHTS）的新型 sGC 刺激剂的发现，该刺激剂来自咪唑并[1,2-a]吡啶先导系列。通过对初始筛选命中物的广泛交错优化，可同时显著改善效力、代谢稳定性、渗透和溶解度等缺陷。这些努力最终发现了新型 sGC 刺激剂 和 。事实证明，BAY 1165747（BAY-747， ）可能是高血压患者的理想治疗选择，尤其是那些对标准抗高血压治疗（耐药性高血压）无反应的患者。在 1 期研究中，BAY-747（ ）表现出长达 24 小时的持续血液动力学效应。
