The synthesis of novel GABA uptake inhibitors. 1. Elucidation of the structure-activity studies leading to the choice of (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (tiagabine) as an anticonvulsant drug candidate.
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/heteroaromatic groups. The majority of the compounds described are structurally related to tiagabine, (R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3- piperidinecarboxylic acid hydrochloride (NNC 05-0328) and some of the reasoning behind the selection of this compound as a drug candidate is summarized.
Pharmaceuticals Division, Novo Nordisk A/S, Måløv, Denmark.
K E
KE
Andersen
C
C
Braestrup
F C
FC
Grønwald
A S
AS
Jørgensen
E B
EB
Nielsen
U
U
Sonnewald
P O
PO
Sørensen
P D
PD
Suzdak
L J
LJ
Knutsen
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018756:GABA Antagonists; D015394:Molecular Structure; D009539:Nicotinic Acids / Q000737:chemistry; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives*; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000078308:Tiagabine; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000927:Anticonvulsants; D018756:GABA Antagonists; D009539:Nicotinic Acids; D009557:Nipecotic Acids; C030278:nipecotic acid; C015910:guvacine; D005680:gamma-Aminobutyric Acid; D011392:Proline; C010983:homoproline; D000078308:Tiagabine