Stereospecific synthesis and structure-activity relationships of unsymmetrical 4,4-diphenylbut-3-enyl derivatives of nipecotic acid as GAT-1 inhibitors.
Two complementary stereospecific synthetic approaches for the preparation of unsymmetrical ortho-substituted N-(4,4-diphenylbut-3-enyl) derivatives of nipecotic acid are described. Determination of the activity of the prepared compounds at the GAT-1 transporter highlighted differing SAR requirements of the E- and Z-phenyl rings, and led to the discovery of a compound with comparable potency to tiagabine. Some attempts to replace nipecotic acid with alternative novel amino acids are also described.
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, Via A Fleming 4, 37135 Verona, Italy. domenica.a.pizzi@gsk.com
Domenica A
DA
Pizzi
Colin P
CP
Leslie
Romano
R
Di Fabio
Catia
C
Seri
Giovanni
G
Bernasconi
Michela
M
Squaglia
Gennaro
G
Carnevale
Alessandro
A
Falchi
Elisabetta
E
Greco
Laura
L
Mangiarini
Michele
M
Negri
D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D058805:GABA Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009557:Nipecotic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids