Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults.
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.
Erondu
Ngozi
N
Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey 07065.
Gantz
Ira
I
Musser
Bret
B
Suryawanshi
Shailaja
S
Mallick
Madhuja
M
Addy
Carol
C
Cote
Josee
J
Bray
George
G
Fujioka
Ken
K
Bays
Harold
H
Hollander
Priscilla
P
Sanabria-Bohórquez
Sandra M
SM
Eng
WaiSi
W
Långström
Bengt
B
Hargreaves
Richard J
RJ
Burns
H Donald
HD
Kanatani
Akio
A
Fukami
Takehiro
T
MacNeil
Douglas J
DJ
Gottesdiener
Keith M
KM
Amatruda
John M
JM
Kaufman
Keith D
KD
Heymsfield
Steven B
SB
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
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-