2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2016 Jul 1;26(13):3207-3211. doi: 10.1016/j.bmcl.2016.03.096.
Dmitry O Koltun 1,  Eric Q Parkhill 1,  Elfatih Elzein 1,  Tetsuya Kobayashi 1,  Robert H Jiang 1,  Xiaofen Li 1,  Thao D Perry 1,  Belem Avila 1,  Wei-Qun Wang 2,  Ryoko Hirakawa 2,  Catherine Smith-Maxwell 2,  Lin Wu 2,  Arvinder K Dhalla 2,  Sridharan Rajamani 2,  Nevena Mollova 3,  Brian Stafford 3,  Jennifer Tang 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., 7601 Dumbarton Cir, Fremont, CA 94555, USA.
  • 3 Department of Drug Metabolism, Gilead Sciences Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
PMID: 27038498 DOI: 10.1016/j.bmcl.2016.03.096
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.

Keywords

Angina; Anti-ischemic; GS-462808; Late I(Na) current inhibitor; Ranolazine.

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