Design, Synthesis, and Structure鈥揂ctivity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors
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- 作者：Jeremy Green ; Jingrong Cao ; Upul K. Bandarage ; Huai Gao ; John Court ; Craig Marhefka ; Marc Jacobs ; Paul Taslimi ; David Newsome ; Tomoko Nakayama ; Sundeep Shah ; Steve Rodems
- 刊名：Journal of Medicinal Chemistry
- 出版年：2015
- 出版时间：June 25, 2015
- 年：2015
- 卷：58
- 期：12
- 页码：5028-5037
- 全文大小：497K
- ISSN：1520-4804
文摘
The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation.