Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists.
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
Leslie
Colin P
CP
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline SpA, Medicines Research Centre, Verona, Italy. colin.p.leslie@gsk.com
Bentley
Jonathan
J
Biagetti
Matteo
M
Contini
Stefania
S
Di Fabio
Romano
R
Donati
Daniele
D
Genski
Thorsten
T
Guery
Sebastien
S
Mazzali
Angelica
A
Merlo
Giancarlo
G
Pizzi
Domenica A
DA
Sacco
Fabiola
F
Seri
Catia
C
Tessari
Michela
M
Zonzini
Laura
L
Caberlotto
Laura
L
D000818:Animals; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; D003577:Cytochrome P-450 Enzyme System