1. Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
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Steven B. Heymsfield, Carol Addy, Richard Hargreaves, Bengt Långström, Keith Gottesdiener, Wai-Si Eng, Takehiro Fukami, Priscilla Hollander, Josee Cote, John M. Amatruda, Ira Gantz, Ken Fujioka, Keith D. Kaufman, H. Donald Burns, Ngozi Erondu, Shailaja Suryawanshi, George A. Bray, Sandra M. Sanabria-Bohórquez, Akio Kanatani, Bret J. Musser, Madhuja Mallick, Harold Bays, and Douglas J. MacNeil
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Adult ,medicine.medical_specialty ,Adolescent ,Physiology ,HUMDISEASE ,Neuropeptide ,Administration, Oral ,Pharmacology ,Overweight ,Sensitivity and Specificity ,MOLNEURO ,Placebos ,Structure-Activity Relationship ,Double-Blind Method ,Weight loss ,Cyclohexanes ,Internal medicine ,Orexigenic ,Medicine ,Humans ,Spiro Compounds ,Obesity ,Receptor ,Molecular Biology ,Aged ,Dose-Response Relationship, Drug ,Molecular Structure ,business.industry ,Body Weight ,Antagonist ,Cell Biology ,Middle Aged ,Neuropeptide Y receptor ,Blockade ,Receptors, Neuropeptide Y ,Endocrinology ,Treatment Outcome ,CHEMBIO ,Positron-Emission Tomography ,Pyrazoles ,Anti-Obesity Agents ,medicine.symptom ,business ,medicine.drug - Abstract
SummaryNeuropeptide 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.
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