1354198-55-2Relevant academic research and scientific papers
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
Koltun, Dmitry O.,Parkhill, Eric Q.,Elzein, Elfatih,Kobayashi, Tetsuya,Jiang, Robert H.,Li, Xiaofen,Perry, Thao D.,Avila, Belem,Wang, Wei-Qun,Hirakawa, Ryoko,Smith-Maxwell, Catherine,Wu, Lin,Dhalla, Arvinder K.,Rajamani, Sridharan,Mollova, Nevena,Stafford, Brian,Tang, Jennifer,Belardinelli, Luiz,Zablocki, Jeff A.
, p. 3207 - 3211 (2016/06/13)
Previously we disclosed the discovery of potent Late INa current inhibitor 2 (GS-458967, IC50 of 333 nM) 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 84 ?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 7 day rat toxicology studies.
Fused Heterocyclic Compounds as Ion Channel Modulators
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Page/Page column 56; 59; 77; 79, (2012/01/15)
The present disclosure relates to compounds that are sodium channel inhibitors and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes. In particular embodiments, the structure of the compounds is given by Formula I: wherein R1, R2, R3, R4, and R5 are as described herein, to methods for the preparation and use of the compounds and to pharmaceutical compositions containing the same.
