Discovery Of Triazolopyridine Gs-458967, A Late Sodium Current Inhibitor (Late I(Na)I) Of The Cardiac Na-V 1.5 Channel With Improved Efficacy And Potency Relative To Ranolazine

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and beta-blocker activity and identified [1,2,4]triazolo[4,3-alpha]pyridine as an early lead. Optimization of substituents for Late I-Na current inhibition and lack of Peak INa inhibition led to the discovery of 4h (GS-458967) with improved anti- arrhythmic activity relative to ranolazine. Unfortunately, 4h demonstrated use dependent block across the sodium isoforms including the central and peripheral nervous system isoforms that is consistent with its low therapeutic index (approximately 5-fold in rat, 3-fold in dog). Compound 4h represents our initial foray into a 2nd generation Late I-Na inhibitor program and is an important proof-of-concept compound. We will provide additional reports on addressing the CNS challenge in a follow-up communication. (C) 2016 Elsevier Ltd. All rights reserved.