2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2016 Jul 1;26(13):3202-3206. doi: 10.1016/j.bmcl.2016.03.101.
Dmitry O Koltun 1,  Eric Q Parkhill 1,  Elfatih Elzein 1,  Tetsuya Kobayashi 1,  Gregory T Notte 1,  Rao Kalla 1,  Robert H Jiang 1,  Xiaofen Li 1,  Thao D Perry 1,  Belem Avila 1,  Wei-Qun Wang 2,  Catherine Smith-Maxwell 2,  Arvinder K Dhalla 2,  Sridharan Rajamani 2,  Brian Stafford 3,  Jennifer Tang 3,  Nevena Mollova 3,  Luiz Belardinelli 2,  Jeff A Zablocki 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
  • 2 Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
  • 3 Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
PMID: 27080178 DOI: 10.1016/j.bmcl.2016.03.101
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.

Keywords

Anti-arrhythmic; GS-458967; Late I(Na) current inhibitor; Ranolazine; Ventricular arrhythmia.

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