Tetrahydroisoquinoline Derivatives As Highly Selective and Potent Rho Kinase Inhibitors

详细信息    查看全文

• 作者：Xingang Fang ; Yan Yin ; Yen Ting Chen ; Lei Yao ; Bo Wang ; Michael D. Cameron ; Li Lin ; Susan Khan ; Claudia Ruiz ; Thomas Schrter ; Wayne Grant ; Amiee Weiser ; Jennifer Pocas ; Alok Pachori ; Stephan Schrer ; P
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 12, 2010
• 年：2010
• 卷：53
• 期：15
• 页码：5727-5737
• 全文大小：970K
• 年卷期：v.53,no.15(August 12, 2010)
• ISSN：1520-4804

文摘

Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure−activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC₅₀ = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.