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.
Pizzi
Domenica Antonia
DA
GlaxoSmithKline, Neurosciences Centre of Excellence for Drug Discovery, Medicines Research Centre, Verona, Italy. Domenica.a.pizzi@gsk.com
Leslie
Colin Philip
CP
Mazzali
Angelica
A
Seri
Catia
C
Biagetti
Matteo
M
Bentley
Jonathan
J
Genski
Thorsten
T
Di Fabio
Romano
R
Contini
Stefania
S
Sabbatini
Fabio Maria
FM
Zonzini
Laura
L
Caberlotto
Laura
L
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