Document Report Card

ID: ALA1139217

Journal: J Med Chem

Title: Development of dihydropyridone indazole amides as selective Rho-kinase inhibitors.

Authors: Goodman KB, Cui H, Dowdell SE, Gaitanopoulos DE, Ivy RL, Sehon CA, Stavenger RA, Wang GZ, Viet AQ, Xu W, Ye G, Semus SF, Evans C, Fries HE, Jolivette LJ, Kirkpatrick RB, Dul E, Khandekar SS, Yi T, Jung DK, Wright LL, Smith GK, Behm DJ, Bentley R, Doe CP, Hu E, Lee D.

Abstract: 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.

CiteXplore: 17201405

DOI: 10.1021/jm0609014