Goodman Krista B, Cui Haifeng, Dowdell Sarah E, Gaitanopoulos Dimitri E, Ivy Robert L, Sehon Clark A, Stavenger Robert A, Wang Gren Z, Viet Andrew Q, Xu Weiwei, Ye Guosen, Semus Simon F, Evans Christopher, Fries Harvey E, Jolivette Larry J, Kirkpatrick Robert B, Dul Edward, Khandekar Sanjay S, Yi Tracey, Jung David K, Wright Lois L, Smith Gary K, Behm David J, Bentley Ross, Doe Christopher P, Hu Erding, Lee Dennis
Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
J Med Chem. 2007 Jan 11;50(1):6-9. doi: 10.1021/jm0609014.
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.
Rho激酶（ROCK1）介导血管平滑肌收缩，是治疗高血压及相关疾病的潜在靶点。吲唑酰胺3被鉴定为一种强效且选择性的ROCK1抑制剂，但口服生物利用度较差。对该先导化合物进行优化后发现了一系列二氢吡啶类化合物，以13为代表，其药代动力学参数相对于初始先导化合物有所改善。吲唑取代在降低清除率和提高口服生物利用度方面起关键作用。
