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

• Published in: Journal of medicinal chemistry 1999-10, Vol.42 (21), p.4281-4291
• Main Authors: Andersen, Knud Erik, Sørensen, Jan L, Huusfeldt, Per O, Knutsen, Lars J. S, Lau, Jesper, Lundt, Behrend F, Petersen, Hans, Suzdak, Peter D, Swedberg, Michael D. B
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Female; gamma-Aminobutyric Acid - metabolism; In Vitro Techniques; Medical sciences; Neuropharmacology; Neurotransmitter Uptake Inhibitors - chemical synthesis; Neurotransmitter Uptake Inhibitors - chemistry; Neurotransmitter Uptake Inhibitors - pharmacology; Nipecotic Acids - chemical synthesis; Nipecotic Acids - chemistry; Nipecotic Acids - pharmacology; Pharmacology. Drug treatments; Rats; Seizures - physiopathology; Structure-Activity Relationship; Synaptosomes - drug effects; Synaptosomes - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980492e

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 [3H]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-piperidinecarboxylic 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-β-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).