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ID: ALA4011647
Journal: J Med Chem
Title: Potent Body Weight-Lowering Effect of a Neuromedin U Receptor 2-selective PEGylated Peptide.
Authors: Kanematsu-Yamaki Y, Nishizawa N, Kaisho T, Nagai H, Mochida T, Asakawa T, Inooka H, Dote K, Fujita H, Matsumiya K, Hirabayashi H, Sakamoto J, Ohtaki T, Takekawa S, Asami T.
Abstract: 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.
CiteXplore: 28657315