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Dihydropyridine neuropeptide Y Y(1) receptor antagonists
Graham S Poindexter1, Marc A Bruce, Karen L LeBoulluec
1Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, 06492-7660, Wallingford, CT 06492-7660, USA. graham.poindexter@bms.com
Abstract:
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).