Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors.
The identification of a new class of potent and selective ROCK-II inhibitors is presented. Compound 5 (SR-3677) had an IC 50 of approximately 3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacology studies showed that 5 was efficacious in both, increasing ex vivo aqueous humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation.
Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Florida, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
Yangbo
Y
Feng
Yan
Y
Yin
Amiee
A
Weiser
Evelyn
E
Griffin
Michael D
MD
Cameron
Li
L
Lin
Claudia
C
Ruiz
Stephan C
SC
Schürer
Toshihiro
T
Inoue
P Vasanth
PV
Rao
Thomas
T
Schröter
Philip
P
Lograsso
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004146:Dioxanes / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D013552:Swine; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D004146:Dioxanes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D054460:rho-Associated Kinases