Development of Dihydropyridone Indazole
Amides as Selective Rho-Kinase Inhibitors

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

doi:10.1021/jm0609014.s001

Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors

journal contribution

posted on 2007-01-11, 00:00 authored by Krista B. Goodman, Haifeng Cui, Sarah E. Dowdell, Dimitri E. Gaitanopoulos, Robert L. Ivy, Clark A. Sehon, Robert A. Stavenger, Gren Z. Wang, Andrew Q. Viet, Weiwei Xu, Guosen Ye, Simon F. Semus, Christopher Evans, Harvey E. Fries, Larry J. Jolivette, Robert B. Kirkpatrick, Edward Dul, Sanjay S. Khandekar, Tracey Yi, David K. Jung, Lois L. Wright, Gary K. Smith, David J. Behm, Ross Bentley, Christopher P. Doe, Erding Hu, Dennis Lee

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.