110283-70-0Relevant academic research and scientific papers
The Synthesis of Novel GABA Uptake Inhibitors. 1. Elucidation of the Structure-Activity Studies Leading to the Choice of (R)-1--3-piperidinecarboxylic Acid (Tiagabine) as an Anticonvulsant Drug Candidate
Andersen, Knud Erik,Braestrup, Claus,Groenwald, Frederik C.,Joergensen, Anker S.,Nielsen, Erik B.,et al.
, p. 1716 - 1725 (2007/10/02)
A series of different synthetic approaches to novel GABA uptake inhibitors are described, leading to examples which are derivatives of nipecotic acid and guvacine, substituted at nitrogen by 4,4-diaryl-3-butenyl or 2-(diphenylmethoxy)ethyl moieties.The in vitro value for inhibition of 3H>-GABA uptake in rat synaptosomes was determined for each compound.It was found that the most potent examples are those having a substituent in an "ortho" position in one or both aromatic/heteroatomic groups.The majority of the compounds described are structurally related to tiagabine, (R)-1--3-piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.
Structure-Activity Studies on Benzhydrol-Containing Nipecotic Acid and Guvacine Derivatives as Potent, Orally-Active Inhibitors of GABA Uptake
Pavia, Michael R.,Lobbestael, Sandra J.,Nugiel, David,Mayhugh, Daniel R.,Gregor, Vlad E.,et al.
, p. 4238 - 4248 (2007/10/02)
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 μM (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.
