Structure–activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II

6533b82bfe1ef96bd128e372

RESEARCH PRODUCT

Structure–activity relationships, and drug metabolism and pharmacokinetic properties for indazole piperazine and indazole piperidine inhibitors of ROCK-II

Evelyn Griffin Bozena Frackowiak Michael D. Cameron Yangbo Feng Li Lin Thomas Schröter Philip Lograsso Claudia Ruiz

subject

Kinase Indazoles Inhibitor Stereochemistry Clinical Biochemistry Pharmaceutical Science Protein Serine-Threonine Kinases Pharmacology Biochemistry Piperazines Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Drug Stability Piperidines In vivo Drug Discovery Animals Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme Inhibitors Humans Structure–activity relationship Pharmacokinetics Rho-kinase Protein Kinase Inhibitors Molecular Biology Cytochrome P-450 Enzyme Inhibitors rho-Associated Kinases Indazole CYP3A4 Organic Chemistry Intracellular Signaling Peptides and Proteins ROCK-II Rats Piperazine Pharmaceutical Preparations chemistry Molecular Medicine Piperidine Drug metabolism

description

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 IC50s 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.

year	journal	country	edition	language
2007-04-01	Bioorganic & Medicinal Chemistry Letters : a tetrahedron publication for the rapid dissemination of preliminary communication and all aspects of bioorganic chemistry, medicinal chemistry and related disciplines

10.1016/j.bmcl.2006.12.043 https://doi.org/10.1016/j.bmcl.2006.12.043