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 IC50 of ∼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. RhoA and its downstream kinase (ROCK) play an important role in the regulation of smooth muscle contraction 1 and neurite growth retraction. 2 The abnormal activation of the ROCK pathway has also been observed in many disorders of the central nervous system. 3 Therefore, the inhibition of ROCK is a promising strategy for the treatment of various diseases such as hypertension, 4 coronary and cerebral vasospasm, 5 erectile dysfunction, 6 glaucoma, 7,8 asthma, 9 multiple sclerosis (MS), 3 atherosclerosis, 10 stroke, 11 and cancer. 12