title: Discovery and evaluation of spirocyclic derivatives as antagonists of the neuropeptide Y5 receptor.
abstract: A novel series of spirocyclic derivatives was synthesized and evaluated as NPY Y5R antagonists for the treatment of obesity. Cis and trans analogs 7a and 8a were equipotent in a Y5R binding assay (K(i)'s ≤ 1 nM) and displayed good stability in human and rat liver microsome preparations. Compound 7a failed to demonstrate weight loss activity in a diet-induced obese (DIO) rat model at unbound drug levels in the brain that exceeded the Y5R K(i) value by 25-fold over a 24-h time-period.
authors.affiliation: Department of Worldwide Medicinal Chemistry, Pfizer PharmaTherapeutics, Groton, CT 06340, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Fichtner
authors.forename: Eunsun
authors.initials: E
authors.lastname: Lee
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Tomlinson
authors.forename: Dennis
authors.initials: D
authors.lastname: Scott
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelius
authors.forename: Terrell A
authors.initials: TA
authors.lastname: Patterson
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000737:chemistry / Q000494:pharmacology; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D055808:Drug Discovery; D004355:Drug Stability; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019440:Anti-Obesity Agents; D003510:Cyclohexanes; D011720:Pyrazoles; D017476:Receptors, Neuropeptide Y; D013141:Spiro Compounds; C100568:neuropeptide Y5 receptor; C515547:spiro(cyclohexane-1,3'(1'H)-furo(3,4-C)pyridine)-4-carboxamide, N-(1-(2-fluorophenyl)-1h-pyrazol-3-yl)-1'-oxo-, trans-