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.
Feng
Yangbo
Y
Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Florida, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
Yin
Yan
Y
Weiser
Amiee
A
Griffin
Evelyn
E
Cameron
Michael D
MD
Lin
Li
L
Ruiz
Claudia
C
Schürer
Stephan C
SC
Inoue
Toshihiro
T
Rao
P Vasanth
PV
Schröter
Thomas
T
Lograsso
Philip
P
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