Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma

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• 作者：Jill M. Sturdivantp> ; p>p>jsturdivant@aeriepharma.com" class="auth_mail" title="E-mail the corresponding authorp> ; Susan M. Royalty ; Cheng-Wen Lin ; Lori A. Moore ; Jeffrey D. Yingling ; Carmen L. Laethem ; Bryan Sherman ; Geoffrey R. Heintzelman ; Casey C. Kopczynski ; Mitchell A. deLong
• 关键词：OURRXQUGYQRVML-UHFFFAOYSA-N
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 May 2016
• 年：2016
• 卷：26
• 期：10
• 页码：2475-2480
• 全文大小：894 K

文摘

Inhibition of Rho kinase (ROCK) to improve fluid outflow through the trabecular meshwork and lower intraocular pressure is a strategy for the development of new anti-glaucoma agents. Alpha-aryl-beta-amino isoquinoline analogs were identified as potent ROCK inhibitors. Compounds that provided a longer duration of intraocular pressure reduction in Dutch Belted rabbits also inhibited norepinephrine transporter. Ester 60 improved bioavailability of its parent ROCK inhibitor, 29 (K_i = 0.2 nM) and demonstrated an effective and sustained IOP reduction for 24 h after dosing. From these studies, netarsudil (a.k.a. AR-13324) was discovered and is currently in clinical trials for the treatment of glaucoma and ocular hypertension.