Dihydropyridine neuropeptide Y Y(1) receptor antagonists.
Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).
Poindexter
Graham S
GS
Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, 06492-7660, Wallingford, CT 06492-7660, USA. graham.poindexter@bms.com
Bruce
Marc A
MA
LeBoulluec
Karen L
KL
Monkovic
Ivo
I
Martin
Scott W
SW
Parker
Eric M
EM
Iben
Larry G
LG
McGovern
Rachel T
RT
Ortiz
Astrid A
AA
Stanley
Jennifer A
JA
Mattson
Gail K
GK
Kozlowski
Michael
M
Arcuri
Meredith
M
Antal-Zimanyi
Ildiko
I
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; C456407:BMS 193885; D004095:Dihydropyridines; D010671:Phenylurea Compounds; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor