Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.

Abstract

We started with a medium throughput screen of heterocyclic compounds without basic amine groups to avoid hERG and β-blocker activity and identified [1,2,4]triazolo[4,3-a]pyridine as an early lead. Optimization of substituents for Late INa 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 INa 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.

DOI: 10.1016/j.bmcl.2016.03.101

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Cite this paper

@article{Koltun2016DiscoveryOT, title={Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine.}, author={Dmitry O Koltun and Eric Q Parkhill and Elfatih O Elzein and Tetsuya Kobayashi and Gregory T Notte and Rao V. Kalla and Robert H Jiang and Xiaofen Li and Thao D Perry and Belem Avila and Wei-Qun Wang and Catherine Smith-Maxwell and Arvinder K. Dhalla and Sridharan Rajamani and Brian Stafford and Jennifer H Tang and Nevena Mollova and Luiz Belardinelli and Jeff A. Zablocki}, journal={Bioorganic & medicinal chemistry letters}, year={2016}, volume={26 13}, pages={3202-3206} }