Discovery of IWP-051, a Novel Orally Bioavailable sGC Stimulator with Once-Daily Dosing Potential in Humans

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• 作者：Takashi Nakai ; Nicholas R. Perl ; Timothy C. Barden ; Andrew Carvalho ; Angelika Fretzen ; Peter Germano ; G-Yoon J. Im ; Hong Jin ; Charles Kim ; Thomas W.-H. Lee ; Kimberly Long ; Joel Moore ; Jason M. Rohde ; Renee Sarno ; Chrissie Segal ; Erik O. Solberg ; Jenny Tobin ; Daniel P. Zimmer ; Mark G. Currie
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：May 12, 2016
• 年：2016
• 卷：7
• 期：5
• 页码：465-469
• 全文大小：331K
• 年卷期：0
• ISSN：1948-5875

文摘

In recent years, soluble guanylate cyclase (sGC, EC 4.6.1.2) has emerged as an attractive therapeutic target for treating cardiovascular diseases and diseases associated with fibrosis and end-organ failure. Herein, we describe our design and synthesis of a series of 4-hydroxypyrimidine sGC stimulators starting with an internally discovered lead. Our efforts have led to the discovery of IWP-051, a molecule that achieves good alignment of potency, stability, selectivity, and pharmacodynamic effects while maintaining favorable pharmacokinetic properties with once-daily dosing potential in humans.