Drug Discovery, Bayer AG , Aprather Weg 18a, 42113 Wuppertal, Germany.
J Med Chem. 2017 Jun 22;60(12):5146-5161. doi: 10.1021/acs.jmedchem.7b00449. Epub 2017 Jun 12.
The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.
利奥西呱是一种首创的可溶性鸟苷酸环化酶（sGC）刺激剂，最近被引入肺动脉高压的新型治疗选择。尽管具有出色的药理学特性，但由于半衰期短，利奥西呱在其他心血管适应症中的应用受到限制，需要每日三次给药。在进一步优化化合物类别的努力中，我们发现了有趣的构效关系，并能够显著降低氧化代谢。这些研究导致了每日一次的 sGC 刺激剂维立西呱（化合物 24，BAY 1021189）的发现，目前正在进行慢性心力衰竭的 3 期临床试验，现将其研究结果报告如下。
