title: Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities.
abstract: 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.
authors.affiliation: Department of Investigational Biology, Centres of Excellence for Cardiovascular Urogenital Drug Discovery, Discovery Research, GlaxoSmithKline Pharmaceuticals Inc., King of Prussia, PA 19406, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Doe
authors.forename: Ross
authors.initials: R
authors.lastname: Bentley
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Robert
authors.initials: R
authors.lastname: Lafferty
authors.forename: Robert
authors.initials: R
authors.lastname: Stavenger
authors.forename: David
authors.initials: D
authors.lastname: Jung
authors.forename: Mark
authors.initials: M
authors.lastname: Bamford
authors.forename: Terry
authors.initials: T
authors.lastname: Panchal
authors.forename: Eugene
authors.initials: E
authors.lastname: Grygielko
authors.forename: Lois L
authors.initials: LL
authors.lastname: Wright
authors.forename: Gary K
authors.initials: GK
authors.lastname: Smith
authors.forename: Zunxuan
authors.initials: Z
authors.lastname: Chen
authors.forename: Christine
authors.initials: C
authors.lastname: Webb
authors.forename: Sanjay
authors.initials: S
authors.lastname: Khandekar
authors.forename: Tracey
authors.initials: T
authors.lastname: Yi
authors.forename: Robert
authors.initials: R
authors.lastname: Kirkpatrick
authors.forename: Edward
authors.initials: E
authors.lastname: Dul
authors.forename: Larry
authors.initials: L
authors.lastname: Jolivette
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
authors.forename: Robert
authors.initials: R
authors.lastname: Willette
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
authors.forename: Erding
authors.initials: E
authors.lastname: Hu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
chemical_list: C516970:4-(7-((3-amino-1-pyrrolidinyl)carbonyl)-1-ethyl-1H-imidazo(4,5-c)pyridin-2-yl)-1,2,5-oxadiazol-3-amine; D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D016207:Cytokines; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; C516969: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; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; D017346:Protein Serine-Threonine Kinases; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases