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.
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.
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Dmitry O
authors.initials: DO
authors.lastname: Koltun
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Eric Q
authors.initials: EQ
authors.lastname: Parkhill
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Elfatih
authors.initials: E
authors.lastname: Elzein
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Notte
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Rao
authors.initials: R
authors.lastname: Kalla
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Jiang
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Thao D
authors.initials: TD
authors.lastname: Perry
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Belem
authors.initials: B
authors.lastname: Avila
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Smith-Maxwell
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Stafford
authors.affiliation: Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Nevena
authors.initials: N
authors.lastname: Mollova
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 333, Fremont, CA 94555, USA.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Department of Medicinal Chemistry, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Jeff A
authors.initials: JA
authors.lastname: Zablocki
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D000069458:Ranolazine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D051638:Ether-A-Go-Go Potassium Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011725:Pyridines; D026941:Sodium Channel Blockers; D014230:Triazoles; D000069458:Ranolazine
keywords: Anti-arrhythmic; GS-458967; Late I(Na) current inhibitor; Ranolazine; Ventricular arrhythmia