Synthesis and Biological Evaluation of Urea Derivatives as Highly Potent and Selective Rho Kinase Inhibitors

详细信息    查看全文

• 作者：Yan Yin ; Li Lin ; Claudia Ruiz ; Susan Khan ; Michael D. Cameron ; Wayne Grant ; Jennifer Pocas ; Nibal Eid ; HaJeung Park ; Thomas Schr枚ter ; Philip V. LoGrasso ; Yangbo Feng
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3568-3581
• 全文大小：551K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

RhoA and its downstream effector ROCK mediate stress fiber formation and cell contraction through their effects on the phosphorylation of myosin light chain (MLC). Inhibition of the RhoA/ROCK pathway has proven to be a promising strategy for several indications such as cardiovascular disease, glaucoma, and inflammatory disease. In 2010, our group reported urea-based ROCK inhibitors as potential antiglaucoma agents. These compounds showed potent IC₅₀ values in enzymatic and cell-based assays and significant intraocular pressure (IOP)-lowering effects in rats (7 mmHg).(22) To develop more advanced ROCK inhibitors targeting various potential applications (such as myocardial infarction, erectile dysfunction, multiple sclerosis, etc.) in addition to glaucoma, a thorough SAR for this urea-based scaffold was studied. The detailed optimization process, counter-screening, and in vitro and in vivo DMPK studies are discussed. Potent and selective ROCK inhibitors with various in vivo pharmacokinetic properties were discovered.