title: Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults.
abstract: Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
authors.affiliation: Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065.
authors.forename: Ngozi
authors.initials: N
authors.lastname: Erondu
authors.forename: Ira
authors.initials: I
authors.lastname: Gantz
authors.forename: Bret
authors.initials: B
authors.lastname: Musser
authors.forename: Shailaja
authors.initials: S
authors.lastname: Suryawanshi
authors.forename: Madhuja
authors.initials: M
authors.lastname: Mallick
authors.forename: Carol
authors.initials: C
authors.lastname: Addy
authors.forename: Josee
authors.initials: J
authors.lastname: Cote
authors.forename: George
authors.initials: G
authors.lastname: Bray
authors.forename: Ken
authors.initials: K
authors.lastname: Fujioka
authors.forename: Harold
authors.initials: H
authors.lastname: Bays
authors.forename: Priscilla
authors.initials: P
authors.lastname: Hollander
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria-Bohórquez
authors.forename: WaiSi
authors.initials: W
authors.lastname: Eng
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: MacNeil
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.forename: John M
authors.initials: JM
authors.lastname: Amatruda
authors.forename: Keith D
authors.initials: KD
authors.lastname: Kaufman
authors.forename: Steven B
authors.initials: SB
authors.lastname: Heymsfield
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001835:Body Weight; D003510:Cyclohexanes / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D010919:Placebos; D049268:Positron-Emission Tomography / Q000379:methods; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012680:Sensitivity and Specificity; D013141:Spiro Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
chemical_list: D019440:Anti-Obesity Agents; D003510:Cyclohexanes; D010919:Placebos; 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-