| Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities. | |
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MedLine Citation:
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PMID: 17018693 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Increased Rho kinase (ROCK) activity contributes to smooth muscle contraction and regulates blood pressure homeostasis. We hypothesized that potent and selective ROCK inhibitors with novel structural motifs would help elucidate the functional role of ROCK and further explore the therapeutic potential of ROCK inhibition for hypertension. In this article, we characterized two aminofurazan-based inhibitors, GSK269962A [N-(3-{[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo[4, 5-c]pyridin-6-yl]oxy}phenyl)-4-{[2-(4-morpholinyl)ethyl]-oxy}benzamide] and SB-7720770-B [4-(7-{[(3S)-3-amino-1-pyrrolidinyl]carbonyl}-1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-amine], as members of a novel class of compounds that potently inhibit ROCK enzymatic activity. GSK269962A and SB-772077-B have IC50 values of 1.6 and 5.6 nM toward recombinant human ROCK1, respectively. GSK269962A also exhibited more than 30-fold selectivity against a panel of serine/threonine kinases. In lipopolysaccharide-stimulated monocytes, these inhibitors blocked the generation of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha. Furthermore, both SB-772077-B and GSK269962A induced vasorelaxation in preconstricted rat aorta with an IC50 of 39 and 35 nM, respectively. Oral administration of either GSK269962A or SB-772077-B produced a profound dose-dependent reduction of systemic blood pressure in spontaneously hypertensive rats. At doses of 1, 3, and 30 mg/kg, both compounds induced a reduction in blood pressure of approximately 10, 20, and 50 mm Hg. In addition, administration of SB-772077-B also dramatically lowered blood pressure in DOCA salt-induced hypertensive rats. SB-772077-B and GSK269962A represent a novel class of ROCK inhibitors that have profound effects in the vasculature and may enable us to further evaluate the potential beneficial effects of ROCK inhibition in animal models of cardiovascular as well as other chronic diseases. |
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Authors:
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Chris Doe; Ross Bentley; David J Behm; Robert Lafferty; Robert Stavenger; David Jung; Mark Bamford; Terry Panchal; Eugene Grygielko; Lois L Wright; Gary K Smith; Zunxuan Chen; Christine Webb; Sanjay Khandekar; Tracey Yi; Robert Kirkpatrick; Edward Dul; Larry Jolivette; Joseph P Marino; Robert Willette; Dennis Lee; Erding Hu |
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Publication Detail:
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Type: Journal Article Date: 2006-10-03 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 320 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2006-12-21 Completed Date: 2007-02-12 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 89-98 Citation Subset: IM |
Affiliation:
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Department of Investigational Biology, Centres of Excellence for Cardiovascular Urogenital Drug Discovery, Discovery Research, GlaxoSmithKline Pharmaceuticals Inc., King of Prussia, PA 19406, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anti-Inflammatory Agents / pharmacology* Antihypertensive Agents / pharmacology Cells, Cultured Cytokines / biosynthesis Humans Imidazoles / pharmacology* Intracellular Signaling Peptides and Proteins / antagonists & inhibitors* Macrophages / drug effects, immunology Male Oxadiazoles / pharmacology* Protein Kinase Inhibitors / pharmacology* Protein-Serine-Threonine Kinases / antagonists & inhibitors* Rats Rats, Inbred SHR Rats, Inbred WKY Vasodilator Agents / pharmacology* rho-Associated Kinases |
| Chemical | |
Reg. No./Substance:
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0/4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine; 0/Anti-Inflammatory Agents; 0/Antihypertensive Agents; 0/Cytokines; 0/Imidazoles; 0/Intracellular Signaling Peptides and Proteins; 0/N-(3-((2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-1H-imidazo(4,5-c)pyridin-6-yl)oxy)phenyl)-4-((2-(4-morpholinyl)ethyl)oxy)benzamide; 0/Oxadiazoles; 0/Protein Kinase Inhibitors; 0/ROCK1 protein, human; 0/Vasodilator Agents; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/rho-Associated Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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