Kanematsu-Yamaki Yoko, Nishizawa Naoki, Kaisho Tomoko, Nagai Hiroaki, Mochida Taisuke, Asakawa Tomoko, Inooka Hiroshi, Dote Katsuko, Fujita Hisashi, Matsumiya Kouta, Hirabayashi Hideki, Sakamoto Junichi, Ohtaki Tetsuya, Takekawa Shiro, Asami Taiji
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd. , Fujisawa, 251-8555, Japan.
J Med Chem. 2017 Jul 27;60(14):6089-6097. doi: 10.1021/acs.jmedchem.7b00330. Epub 2017 Jul 18.
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.
神经介素U（NMU）是一种神经肽，它通过其受体NMU受体1（NMUR1）和NMU受体2（NMUR2）介导多种生理功能。最近，NMU作为糖尿病和肥胖症的一种有前景的治疗选择受到了越来越多的关注。NMU的一种短形式（NMU-8）对两种受体都具有强效激动剂活性，但代谢不稳定。因此，我们通过连接子设计并合成了经聚乙二醇（PEG；分子量20 kDa；PEG20k）修饰的NMU-8类似物。在第19位用3-（2-萘基）丙氨酸取代提高了NMU-8类似物对NMUR2的选择性，同时保留了高激动剂活性。化合物37是一种含有哌嗪-1-基乙酰基连接子的NMUR2选择性PEG20k类似物，在饮食诱导肥胖的小鼠中，通过每日一次重复给药2周，以剂量依赖的方式表现出强效的体重降低作用，同时抑制食物摄入（30 nmol/kg时体重减轻12.4%）。
