Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide,Journal of Medicinal Chemistry

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Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-07-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00330
Yoko Kanematsu-Yamaki ₁ , Naoki Nishizawa ₁ , Tomoko Kaisho ₁ , Hiroaki Nagai ₁ , Taisuke Mochida ₁ , Tomoko Asakawa ₁ , Hiroshi Inooka ₁ , Katsuko Dote ₁ , Hisashi Fujita ₁ , Kouta Matsumiya ₁ , Hideki Hirabayashi ₁ , Junichi Sakamoto ₁ , Tetsuya Ohtaki ₁ , Shiro Takekawa ₁ , Taiji Asami ₁

Affiliation

Neuromedin U (NMU) is a neuropeptide that mediates a variety of physiological functions via its receptors, NMUR1 and NMUR2. Recently, there has been an increased focus on NMU as a promising treatment option for diabetes and obesity. A short form of NMU (NMU-8) has potent agonist activity for both receptors but is metabolically unstable. Therefore, we designed and synthesized NMU-8 analogues modified by polyethylene glycol (PEG; molecular weight, 20 kDa; PEG20k) via a linker. 3-(2-Naphthyl)alanine substitution at position 19 increased NMUR2 selectivity of NMU-8 analogues with retention of high agonist activity. Compound 37, an NMUR2-selective PEG20k analogue containing piperazin-1-ylacetyl linker, exhibited a potent body weight-lowering effect with concomitant inhibition of food intake in a dose-dependent manner (body weight loss of 12.4% at 30 nmol/kg) by once-daily repeated dosing for 2 weeks in mice with diet-induced obesity.

中文翻译：

Neuromedin U受体2-选择性聚乙二醇化肽的有效减肥作用

Neuromedin U（NMU）是一种神经肽，可通过其受体NMUR1和NMUR2介导多种生理功能。最近，人们越来越关注NMU作为糖尿病和肥胖症的有前途的治疗选择。简短形式的NMU（NMU-8）对两种受体均具有有效的激动剂活性，但在代谢上不稳定。因此，我们设计并合成了通过接头修饰的聚乙二醇（PEG;分子量，20 kDa; PEG20k）修饰的NMU-8类似物。19位位置的3-（2-萘基）丙氨酸取代增加了NMU-8类似物的NMUR2选择性，并保留了高激动剂活性。化合物37，一种含有哌嗪-1-基乙酰基接头的NMUR2选择性PEG20k类似物，具有有效的降低体重的作用，并伴随着剂量依赖性地抑制食物摄入（30 nmol / kg时体重减轻12.4％）。饮食诱发肥胖的小鼠每天重复给药2周。

更新日期：2017-07-19

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