Discovery of triazolopyridinone GS-462808, 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: | Elfatih Elzein, Kobayashi Tetsuya, Brian Stafford, Ryoko Hirakawa, Nevena Mollova, Sridharan Rajamani, Belem Avila, Catherine Smith-Maxwell, Thao Perry, Lin Wu, Jennifer Tang, Jeff Zablocki, Xiaofen Li, Wei-Qun Wang, Dmitry Koltun, Parkhill Eric Q, Robert Jiang, Arvinder Dhalla, Luiz Belardinelli |
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| Rok vydání: | 2016 |
| Předmět: |
Azoles
0301 basic medicine Gene isoform Pyridines Sodium Clinical Biochemistry hERG Pharmaceutical Science Ranolazine chemistry.chemical_element Nav1.5 Pharmacology Biochemistry NAV1.5 Voltage-Gated Sodium Channel Structure-Activity Relationship 03 medical and health sciences Dogs 0302 clinical medicine Therapeutic index Drug Discovery medicine Animals Humans Potency Molecular Biology Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Heart Haplorhini Ether-A-Go-Go Potassium Channels Rats 030104 developmental biology medicine.anatomical_structure chemistry Peripheral nervous system biology.protein Molecular Medicine Rabbits 030217 neurology & neurosurgery Sodium Channel Blockers medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:3207-3211 |
| 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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