Development of Dihydropyridone Indazole Amides as Selective Rho-Kinase Inhibitors
- 15 December 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 50 (1), 6-9
- https://doi.org/10.1021/jm0609014
Abstract
Rho kinase (ROCK1) mediates vascular smooth muscle contraction and is a potential target for the treatment of hypertension and related disorders. Indazole amide 3 was identified as a potent and selective ROCK1 inhibitor but possessed poor oral bioavailability. Optimization of this lead resulted in the discovery of a series of dihydropyridones, exemplified by 13, with improved pharmacokinetic parameters relative to the initial lead. Indazole substitution played a critical role in decreasing clearance and improving oral bioavailability.Keywords
This publication has 8 references indexed in Scilit:
- ROCKs: multifunctional kinases in cell behaviourNature Reviews Molecular Cell Biology, 2003
- Molecular Properties That Influence the Oral Bioavailability of Drug CandidatesJournal of Medicinal Chemistry, 2002
- Specificity and mechanism of action of some commonly used protein kinase inhibitorsBiochemical Journal, 2000
- Selective α1a adrenergic receptor antagonists based on 4-aryl-3,4-dihydropyridine-2-onesBioorganic & Medicinal Chemistry Letters, 2000
- H-Series Protein Kinase Inhibitors and Potential Clinical ApplicationsPharmacology & Therapeutics, 1999
- Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertensionNature, 1997
- Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in HumansPharmaceutical Research, 1997
- Novel hexahydrofuro[3,4‐b]‐2(1H)‐pyridones from 4‐aryl substituted 5‐alkoxycarbonyl‐6‐methyl‐3,4‐dihydropyridonesJournal of Heterocyclic Chemistry, 1996