title: Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine.
abstract: Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333nM) that has a good separation of late versus peak Nav1.5 current, but did not have a favorable CNS safety window due to high brain penetration (3-fold higher partitioning into brain vs plasma) coupled with potent inhibition of brain sodium channel isoforms (Nav1.1, 1.2, 1.3). We increased the polar surface area from 50 to 84Å(2) by adding a carbonyl to the core and an oxadiazole ring resulting in 3 GS-462808 that had lower brain penetration and serendipitously lower activity at the brain isoforms. Compound 3 has an improved CNS window (>20 rat and dog) relative to 2, and improved anti-ischemic potency relative to ranolazine. The development of 3 was not pursued due to liver lesions in 7day rat toxicology studies.
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: 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., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
authors.forename: Wei-Qun
authors.initials: WQ
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hirakawa
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Smith-Maxwell
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
authors.affiliation: Department of Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, 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: Nevena
authors.initials: N
authors.lastname: Mollova
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 Biological Sciences, Gilead Sciences Inc., 7601 Dumbarton Cir, 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; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D000882:Haplorhini; D006321:Heart / Q000187:drug effects*; D006801:Humans; 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
chemical_list: D001393:Azoles; D051638:Ether-A-Go-Go Potassium Channels; C000621212:GS-462808; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011725:Pyridines; D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: Angina; Anti-ischemic; GS-462808; Late I(Na) current inhibitor; Ranolazine