Design and Synthesis of 4-Substituted Benzamides as Potent, Selective, and Orally Bioavailable IKs Blockers
- 17 October 2001
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 44 (23) , 3764-3767
- https://doi.org/10.1021/jm015505u
Abstract
Multiple delayed rectifier potassium currents, including IKs, are responsible for the repolarization and termination of the cardiac action potential, and blockers of these currents may be useful as antiarrhythmic agents. Modification of compound 5 produced 19(S) that is the most potent IKs blocker reported to date with >5000-fold selectivity over other cardiac ion channels. Further modification produced 24A with 23% oral bioavailability.Keywords
This publication has 13 references indexed in Scilit:
- Alterations in Ito1, IKrand Ik1Density in the BIO TO-2 Strain of Syrian Myopathic HamstersJournal of Molecular and Cellular Cardiology, 1997
- Class III Antiarrhythmic Activity in Vivo by Selective Blockade of the Slowly Activating Cardiac Delayed Rectifier Potassium Current IKs by (R)-2-(2,4- Trifluoromethyl)-N-[2-oxo-5-phenyl- 1-(2,2,2-trifluoroethyl)-2,3-dihydro- 1H-benzo[e][1,4]diazepin-3-yl]acetamideJournal of Medicinal Chemistry, 1997
- Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channelNature, 1996
- KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium currentNature, 1996
- A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channelCell, 1995
- A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndromeCell, 1995
- Oxadiazoles as Ester Bioisosteric Replacements in Compounds Related to Disoxaril. Antirhinovirus ActivityJournal of Medicinal Chemistry, 1994
- Azines and Imines of 4- and 5-t-Bu-Pyrrole-2-aldehyde. A Useful Synthesis of the AldehydesSynthetic Communications, 1994
- Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.The Journal of general physiology, 1990
- Chemistry of sulfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unitThe Journal of Organic Chemistry, 1977