Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors.
Feng Y,
Yin Y,
Weiser A,
Griffin E,
Cameron MD,
Lin L,
Ruiz C,
Schürer SC,
Inoue T,
Rao PV,
Schröter T,
Lograsso P.
Department of Molecular Therapeutics, and Translational Research Institute, The Scripps Research Institute, Florida, 5353 Parkside Drive, Jupiter, Florida 33458, USA.
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.
PMID: 18834107 [PubMed - indexed for MEDLINE]