1. Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors
- Author
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Larry J. Jolivette, Erding Hu, Andrew Q. Viet, Lois L Wright, Edward Dul, Robert B. Kirkpatrick, Robert A. Stavenger, Haifeng Cui, Weiwei Xu, Gren Z. Wang, David Kendallc Jung, Ross Bentley, David J. Behm, Robert L. Ivy, Dimitri E. Gaitanopoulos, Christopher P. Doe, Tracey Yi, Dennis Lee, Krista B. Goodman, Sarah E. Dowdell, Sanjay S. Khandekar, Gary K Smith, Christopher P. Evans, Guosen Ye, Harvey E. Fries, Simon Semus, and Clark A. Sehon
- Subjects
Models, Molecular ,Indazoles ,Pyridones ,Blood Pressure ,In Vitro Techniques ,Protein Serine-Threonine Kinases ,Muscle, Smooth, Vascular ,Structure-Activity Relationship ,chemistry.chemical_compound ,Rats, Inbred SHR ,Drug Discovery ,Animals ,ROCK1 ,Protein kinase A ,Rho-associated protein kinase ,Antihypertensive Agents ,Aorta ,rho-Associated Kinases ,Indazole ,biology ,Intracellular Signaling Peptides and Proteins ,Amides ,Rats ,Bioavailability ,Pyrimidines ,chemistry ,Biochemistry ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Signal transduction ,Vascular smooth muscle contraction ,Muscle Contraction - 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.
- Published
- 2006
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