Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
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DOI：
10.1016/j.cmet.2006.08.002
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发表时间：
2006-10-01
期刊：
影响因子：
29
通讯作者：
Heymsfield, Steven B.
中科院分区：
文献类型：
--
作者：
Erondu, Ngozi;Gantz, Ira;Heymsfield, Steven B.
神经肽Y （NPY）是一种强效的致氧神经肽，NPY Y1和NPY Y5受体的拮抗作用（NPYxR）被认为是潜在的重要抗肥胖药物靶点。我们使用MIK-0557（一种有效的、高选择性的、口服活性的NPY5R拮抗剂）验证了阻断NPY5R会导致人类体重减轻的假设。本文报道的最初一系列实验，包括多剂量正电子发射断层扫描研究和为期12周的概念验证/剂量范围研究，表明MK-0557的最佳剂量为1mg /天。该假设随后在一项涉及1661名超重和肥胖患者的52周、多中心、随机、双盲、安慰剂对照试验中得到验证。虽然在52周时具有统计学意义，但诱导体重减轻的幅度没有临床意义。这些观察结果首次提供了对人类NPY5R能量稳态途径的临床洞察，并表明在未来的药物开发计划中，仅针对NPY5R不太可能产生治疗效果。
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 MIK-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.