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Abstract #17567 Published in IGR 9-2
Structure-activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II
Feng Y; Cameron MD; Frackowiak B; Griffin E; Lin L; Ruiz C; Schroter T; LoGrasso PBioorganic and Medicinal Chemistry Letters 2007; 17: 2355-2360
ROCK has been implicated in many diseases ranging from glaucoma to spinal cord injury and is therefore an important target for therapeutic intervention. In this study, we have designed a series of 1-(4-(1H-indazol-5-yl)piperazin-1-yl)-2-hydroxy(or 2-amino) analogs and a series of 1-(4-(1H-indazol-5-yl amino)piperidin-1-yl)-2-hydroxy(or 2-amino) inhibitors of ROCK-II. SR-1459 has IC50= 13 nM versus ROCK-II while the IC(50)s for SR-715 and SR-899 are 80 nM and 100 nM, respectively. Many of these inhibitors, especially the 2-amino substituted analogs for both series, are modest/potent CYP3A4 inhibitors as well. However, a few of these inhibitors (SR-715 and SR-899) show strong selectivity for ROCK-II over CYP3A4, but the overall potency of the 2-amino analogs (SR-1459) on CYP3A4 and the high clearance and volume of distribution of these compounds makes the in vivo utility of these analogs undesirable.
Dr. P. LoGrasso, Department of Biochemistry, Department of Drug Discovery, The Scripps Research Institute, 5353 Parkside Drive, RF-2 Jupiter, FL 33458, USA. lograsso@scripps.edu
Classification:
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
