Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake
| Autor: | Charles Taylor, Roy D. Schwarz, Daniel Ray Mayhugh, Vlad E. Gregor, Laura J. Brahce, Sandra J. Lobbestael, Mark G. Vartanian, Michael R. Pavia, David A. Nugiel |
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| Rok vydání: | 1992 |
| Předmět: |
Proline
Stereochemistry medicine.medical_treatment Nipecotic Acids Administration Oral In Vitro Techniques chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Drug Discovery Nipecotic acid Side chain medicine Animals Humans Neurotransmitter Uptake Inhibitors Benzhydryl Compounds gamma-Aminobutyric Acid Chemistry Nicotinic Acids In vitro Rats Guvacine Anticonvulsant Blood-Brain Barrier Molecular Medicine GABA Uptake Inhibitors Anticonvulsants Reuptake inhibitor |
| Zdroj: | Journal of medicinal chemistry. 35(22) |
| ISSN: | 0022-2623 |
| Popis: | The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs. A series of compounds is reported which explores the structure-activity relationships (SAR) in this series. Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring. The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of < 1 microM (including 5, Table I; 37, 43, Table IV; and 44, Table V). Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans. |
| Databáze: | OpenAIRE |
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