A PEGylated analog of short-length Neuromedin U with potent anorectic and anti-obesity effects

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 8; pp. 2307 - 2312
• Main Authors: Inooka, Hiroshi, Sakamoto, Kotaro, Shinohara, Tokuyuki, Masuda, Yasushi, Terada, Michiko, Kumano, Satoshi, Yokoyama, Kotaro, Noguchi, Jiro, Nishizawa, Naoki, Kamiguchi, Hidenori, Fujita, Hisashi, Asami, Taiji, Takekawa, Shiro, Ohtaki, Tetsuya
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.04.2017
• Subjects: Animals; Anti-Obesity Agents - pharmacokinetics; Anti-Obesity Agents - pharmacology; Diabetes; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Neuromedin U (NMU); Neuropeptides - chemistry; Neuropeptides - pharmacokinetics; Neuropeptides - pharmacology; NMU-8; Obesity; Polyethylene glycol (PEG); Polyethylene Glycols - chemistry; Swine; Weight Loss - drug effects; PipPr; Vdss; CNS; C5min; GPT; CHO; γ-Abu; NMU-8; TFA; Neuromedin U (NMU); Aoc; Boc; Aun; AUC0–48h; Obesity; PipAc; Cmax; Achc; DIO; EDTA; Aze; GOT; Acp; PEG; β-Ala; CLtotal; Polyethylene glycol (PEG); NMU; Ape; Tmax; EMCS; Diabetes; Ambz; BA
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.02.023

[Display omitted] Neuromedin U (NMU) is a neuropeptide known to regulate food intake and energy homeostasis that is widely distributed in the gastrointestinal tract, hypothalamus, and pituitary. A short form of NMU, porcine NMU-8 has potent agonist activity for the receptors NMUR1 and NMUR2; however, its short half-life precludes its effective use in vivo. To address this limitation, we designed and synthesized NMU-8 analogs modified by polyethylene glycol (PEG) with a molecular weight of 30kDa (PEG30k) via a variety of linkers (i.e., ω-amino- and ω-imino-carboxylic acid linker). Integrated evaluation of NMUR1 and NMUR2 binding affinities in vitro and anorectic activity in mice revealed that the introduction of a linker with a rigid ring group, e.g., 2-(piperazin-1-yl)acetic acid (PipAc), yielded a highly potent anorectic peptide, PEG30k-PipAc-NMU-8 (14), possessing improved receptor binding affinity. Subsequent optimization of the molecular weight of the PEG moiety led to the discovery of a PEG20k conjugate (15), which exhibited significant anti-obesity effect upon once-daily subcutaneous administration in diet-induced obese mice with 10% and 22% body weight loss at doses of 10 and 30nmol/kg, respectively. In addition, 15 reduced the weights of the liver and adipose tissue in a dose-dependent manner and improved the plasma biochemical parameters, e.g., insulin, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and total cholesterol. Thus, our results suggest that 15 (NMU-0002), which showed potent and long-lasting biological profiles in vivo, represents a candidate peptide for investigating the central and peripheral actions of NMU and its potential for clinical use.