| Literature DB >> 17201405 |
Krista B Goodman1, 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.
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.Entities:
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Year: 2007 PMID： 17201405 DOI： 10.1021/jm0609014
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446