Triazine and pyrimidine based ROCK inhibitors with efficacy in spontaneous hypertensive rat model

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 21; pp. 6027 - 6031
• Main Authors: Ho, Koc-Kan, Beasley, James R., Belanger, Laura, Black, Darcey, Chan, Jui-Hsiang, Dunn, David, Hu, Bing, Klon, Anthony, Kultgen, Steven G., Ohlmeyer, Michael, Parlato, Susan M., Ray, Peter C., Pham, Quynhchi, Rong, Yajing, Roughton, Andrew L., Walker, Tiffany L., Wright, Jane, Xu, Kai, Xu, Yan, Zhang, Limei, Webb, Maria
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.11.2009; Elsevier
• Subjects: Animals; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacology; Binding Sites; Biological and medical sciences; Cardiovascular system; Computer Simulation; Disease Models, Animal; Homology model; Hypertension; Hypertension - drug therapy; Medical sciences; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; ROCK; Structure-Activity Relationship; Triazine; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology; Hypertension; Homology model; Triazine; ROCK; Pyrimidine; Rat; Nitrogen heterocycle; Non-specific serine/threonine protein kinase; Cardiovascular disease; Homology; Selectivity; Modeling; Pyridine derivatives; Signal transduction; Structure activity relation; Six membered ring; Molecular model; Subcutaneous administration; Chemical synthesis; Indan derivatives; Enzyme; Transferases; Rodentia; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; In vivo; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Animal; Triazine derivatives; Antihypertensive agent; Pyrimidine derivatives; Piperazine derivatives
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.09.046

A series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model. The profile of a series of triazine and pyrimidine based ROCK inhibitors is described. An initial binding mode was established based on a homology model and the proposed interactions are consistent with the observed SAR. Compounds from the series are potent in a cell migration assay and possess a favorable kinase selectivity. In vivo activity was demonstrated for compound 1A in a spontaneous hypertensive rat model.