Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists.
A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.
GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicines Research Centre, Verona, Italy. Domenica.a.pizzi@gsk.com
Domenica Antonia
DA
Pizzi
Colin Philip
CP
Leslie
Angelica
A
Mazzali
Catia
C
Seri
Matteo
M
Biagetti
Jonathan
J
Bentley
Thorsten
T
Genski
Romano
R
Di Fabio
Stefania
S
Contini
Fabio Maria
FM
Sabbatini
Laura
L
Zonzini
Laura
L
Caberlotto
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004435:Eating / Q000187:drug effects*; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001562:Benzimidazoles; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor