Discovery of Substituted 4-(Pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as Potent and Highly Selective Rho Kinase (ROCK-II) Inhibitors

Abstract

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.

Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats

“…12 The hydrophobic interaction between the benzodioxane moiety of SR3677 and the hydrophobic pocket under the P-loop of ROCK-II appears to be one of the key elements for its high potency. 12 Its high selectivity was proposed to be mainly due to the H-bond between the protonated tertiary amine of the dimethylaminoethoxy moiety and the carboxylate side chain of Asp176 of ROCK-II. 12 To develop diversified chemotypes as novel ROCK-II inhibitors for the treatment of glaucoma, a urea-based ROCK inhibitor 1a (Figure 1) was recently identified in our group.…”

“…12 Its high selectivity was proposed to be mainly due to the H-bond between the protonated tertiary amine of the dimethylaminoethoxy moiety and the carboxylate side chain of Asp176 of ROCK-II. 12 To develop diversified chemotypes as novel ROCK-II inhibitors for the treatment of glaucoma, a urea-based ROCK inhibitor 1a (Figure 1) was recently identified in our group. In this compound, an achiral benzyl amine moiety was used to replace the chiral 3-substituted benzodioxane group in SR3677.…”

Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity

“…However, based on the overall promising studies showing efficacy of ROCK inhibitors in a variety of animal disease models, there are significant efforts aimed at developing more potent and selective ROCK inhibitors. Recent activities within the pharmaceutical industry and academia have led to a series of novel ROCK inhibitors with enhanced potency within the low nanomolar range and improved kinase selectivity [28][29][30][31][32][33][34]. In addition, as of July 2009, two compounds, RKI983 (Novartis) and INS117548 (Inspire), are in phase I/II studies for the treatment of glaucoma (NCT00846989, NCT00767793).…”

Regulation of Adherens Junctions in Trabecular Meshwork Cells by Rac GTPase and their influence on Intraocular Pressure

“…The AH specimens were frozen until further analysis. Drug concentration in AH specimens was quantified by liquid chromatography-mass spectrometry (LC/MS) analysis [46]. These analyses were done at the Scripps Research Institute, Florida (with the generous help of Dr. Philip Lograsso).…”