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Abstract #26460 Published in IGR 12-3
Tetrahydroisoquinoline derivatives as highly selective and potent rho kinase inhibitors
Fang X; Yin Y; Chen YT; Yao L; Wang B; Cameron MD; Lin L; Khan S; Ruiz C; Schroter TJournal of Medicinal Chemistry 2010; 53: 5727-5737
Rho kinase (ROCK) is a promising drug target for the treatment of many diseases including hypertension, multiple sclerosis, cancer, and glaucoma. The structure-activity relationships (SAR) around a series of tetrahydroisoquinolines were evaluated utilizing biochemical and cell-based assays to measure ROCK inhibition. These novel ROCK inhibitors possess high potency, high selectivity, and appropriate pharmacokinetic properties for glaucoma applications. The lead compound, 35, had subnanomolar potency in enzyme ROCK-II assays as well as excellent cell-based potency (IC(50) = 51 nM). In a kinase panel profiling, 35 had an off-target hit rate of only 1.6% against 442 kinases. Pharmacology studies showed that compound 35 was efficacious in reducing intraocular pressure (IOP) in rats with reasonably long duration of action. These results suggest that compound 35 may serve as a promising agent for further development in the treatment of glaucoma.
P. Lograsso. Translational Research Institute, Department of Molecular Therapeutics, Scripps Research Institute, Florida, 130 Scripps Way, 2A1, Jupiter, FL 33458, United States. lograsso@scripps.edu
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
3.8 Pharmacology (Part of: 3 Laboratory methods)
