Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors

Autor:	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, Clark A. Sehon
Rok vydání:	2006
Předmět:	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
Zdroj:	Journal of Medicinal Chemistry. 50:6-9
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0ebe7de9a4664aed5ef671671bb6c6c0 https://doi.org/10.1021/jm0609014 Zobrazit plný text záznamu