Applications of parallel synthetic lead hopping and pharmacophore-based virtual screening in the discovery of efficient glycine receptor potentiators
| Autor: | Loren Berry, Hakan Gunaydin, Nagasree Chakka, Jeffrey R. Simard, Angel Guzman-Perez, Matthew H. Plant, Erin F. DiMauro, Kristin L. Andrews, Liyue Huang, Jacinthe Gingras, Howard Bregman |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Azetidine Drug Evaluation Preclinical Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Receptors Glycine Aminothiazole Drug Discovery Humans Glycine receptor ADME Pharmacology Sulfonamides Virtual screening Dose-Response Relationship Drug Molecular Structure Drug discovery Chemistry Organic Chemistry General Medicine Potentiator Combinatorial chemistry Molecular Docking Simulation 030104 developmental biology Pharmacophore |
| Zdroj: | European Journal of Medicinal Chemistry. 137:63-75 |
| ISSN: | 0223-5234 |
| Popis: | Glycine receptors (GlyRs) are pentameric glycine-gated chloride ion channels that are enriched in the brainstem and spinal cord where they have been demonstrated to play a role in central nervous system (CNS) inhibition. Herein we describe two novel classes of glycine receptor potentiators that have been developed using similarity- and property-guided scaffold hopping enabled by parallel synthesis and pharmacophore-based virtual screening strategies. This effort resulted in the identification of novel, efficient and modular leads having favorable in vitro ADME profiles and high CNS multi-parameter optimization (MPO) scores, exemplified by azetidine sulfonamide 19 and aminothiazole sulfone (ent2)-20. |
| Databáze: | OpenAIRE |
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