Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late I Na i) of the cardiac Na V 1.5 channel with improved efficacy and potency relative to ranolazine
Autor: | Dmitry O, Koltun, Eric Q, Parkhill, Elfatih, Elzein, Tetsuya, Kobayashi, Gregory T, Notte, Rao, Kalla, Robert H, Jiang, Xiaofen, Li, Thao D, Perry, Belem, Avila, Wei-Qun, Wang, Catherine, Smith-Maxwell, Arvinder K, Dhalla, Sridharan, Rajamani, Brian, Stafford, Jennifer, Tang, Nevena, Mollova, Luiz, Belardinelli, Jeff A, Zablocki |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Pyridines Clinical Biochemistry Pharmaceutical Science Biochemistry NAV1.5 Voltage-Gated Sodium Channel Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Ranolazine Drug Discovery Animals Humans Molecular Biology Dose-Response Relationship Drug Molecular Structure Organic Chemistry Heart Triazoles Ether-A-Go-Go Potassium Channels Rats Macaca fascicularis 030104 developmental biology Microsomes Liver Molecular Medicine Rabbits Caco-2 Cells 030217 neurology & neurosurgery Sodium Channel Blockers |
Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:3202-3206 |
ISSN: | 0960-894X |
Popis: | 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. |
Databáze: | OpenAIRE |
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