Novel Rho kinase inhibitors with anti-inflammatory and vasodilatory activities.
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.
Doe
Chris
C
Department of Investigational Biology, Centres of Excellence for Cardiovascular Urogenital Drug Discovery, Discovery Research, GlaxoSmithKline Pharmaceuticals Inc., King of Prussia, PA 19406, USA.
Bentley
Ross
R
Behm
David J
DJ
Lafferty
Robert
R
Stavenger
Robert
R
Jung
David
D
Bamford
Mark
M
Panchal
Terry
T
Grygielko
Eugene
E
Wright
Lois L
LL
Smith
Gary K
GK
Chen
Zunxuan
Z
Webb
Christine
C
Khandekar
Sanjay
S
Yi
Tracey
T
Kirkpatrick
Robert
R
Dul
Edward
E
Jolivette
Larry
L
Marino
Joseph P
JP
Willette
Robert
R
Lee
Dennis
D
Hu
Erding
E
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
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