title: Synthesis of novel GABA uptake inhibitors. 4. Bioisosteric transformation and successive optimization of known GABA uptake inhibitors leading to a series of potent anticonvulsant drug candidates.
abstract: By bioisosteric transformations and successive optimization of known GABA uptake inhibitors, several series of novel GABA uptake inhibitors have been prepared by different synthetic approaches. These compounds are derivatives of nipecotic acid and guvacine, substituted at the nitrogen of these amino acids by various lipophilic moieties such as diarylaminoalkoxyalkyl or diarylalkoxyalkyl. The in vitro values for inhibition of [(3)H]GABA uptake in rat synaptosomes was determined for each compound, and it was found that the most potent compound from this series, (R)-1-(2-(3,3-diphenyl-1-propyloxy)ethyl)-3-piperidinecarboxyli c acid hydrochloride (29), is so far the most potent parent compound inhibiting GABA uptake into synaptosomes. Structure-activity results confirm our earlier observations, that an electronegative center in the chain connecting the amino acid and diaryl moiety is very critical in order to obtain high in vitro potency. Several of the novel compounds were also evaluated for their ability in vivo to inhibit clonic seizures induced by a 15 mg/kg (ip) dose of methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM). Some of the compounds tested show a high in vivo potency comparable with that of the recently launched anticonvulsant product 6 ((R)-1-(4, 4-bis(3-methyl-2-thienyl)-3-butenyl)-3-piperidinecarboxylic acid).
authors.affiliation: Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK 2760 Måløv, Denmark. kea@novo.dk
authors.forename: K E
authors.initials: KE
authors.lastname: Andersen
authors.forename: J L
authors.initials: JL
authors.lastname: Sørensen
authors.forename: P O
authors.initials: PO
authors.lastname: Huusfeldt
authors.forename: L J
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: J
authors.initials: J
authors.lastname: Lau
authors.forename: B F
authors.initials: BF
authors.lastname: Lundt
authors.forename: H
authors.initials: H
authors.lastname: Petersen
authors.forename: P D
authors.initials: PD
authors.lastname: Suzdak
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000503:physiopathology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C400065:1-DPEPCA hydrochloride; D000927:Anticonvulsants; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid