title: Structure-activity studies on benzhydrol-containing nipecotic acid and guvacine derivatives as potent, orally-active inhibitors of GABA uptake.
abstract: 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.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105-2430.
authors.forename: M R
authors.initials: MR
authors.lastname: Pavia
authors.forename: S J
authors.initials: SJ
authors.lastname: Lobbestael
authors.forename: D
authors.initials: D
authors.lastname: Nugiel
authors.forename: D R
authors.initials: DR
authors.lastname: Mayhugh
authors.forename: V E
authors.initials: VE
authors.lastname: Gregor
authors.forename: C P
authors.initials: CP
authors.lastname: Taylor
authors.forename: R D
authors.initials: RD
authors.lastname: Schwarz
authors.forename: L
authors.initials: L
authors.lastname: Brahce
authors.forename: M G
authors.initials: MG
authors.lastname: Vartanian
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D001812:Blood-Brain Barrier; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D009539:Nicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D051381:Rats; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D001559:Benzhydryl Compounds; D014179:Neurotransmitter Uptake Inhibitors; D009539:Nicotinic Acids; D009557:Nipecotic Acids; C030278:nipecotic acid; C015910:guvacine; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline