Design and synthesis of peptidic partial agonists of human neuromedin U receptor 1 with enhanced serum stability.

Kentaro Takayama, Kenji Mori, Tomo Asari, Yuko Sohma, Erina Nomura, Yu Sasaki, Akihiro Taguchi, Atsuhiko Taniguchi, Mikiya Miyazato, Naoto Minamino, Kenji Kangawa, Yoshio Hayashi

Bioorganic & medicinal chemistry letters 2020 Sep 15

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Neuromedin U (NMU) activates two receptors (NMUR1 and NMUR2) and is a promising candidate for development of drugs to combat obesity. Previously, we obtained hexapeptides as selective full NMUR agonists. Development of a partial agonist which mildly activates receptors is an effective strategy which lead to an understanding of the functions of NMU receptors. In 2014, we reported hexapeptide 3 (CPN-124) as an NMUR1-selective partial agonist but its selectivity and serum stability were unsatisfactory. Herein, we report the development of a hexapeptide-type partial agonist (8, CPN-223) based on a peptide (3) but with higher NMUR1-selectivity and enhanced serum stability. A structure-activity relationship study of synthetic pentapeptide derivatives suggested that a hexapeptide is a minimum structure consistent with both good NMUR1-selective agonistic activity and serum stability. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Kentaro Takayama, Kenji Mori, Tomo Asari, Yuko Sohma, Erina Nomura, Yu Sasaki, Akihiro Taguchi, Atsuhiko Taniguchi, Mikiya Miyazato, Naoto Minamino, Kenji Kangawa, Yoshio Hayashi. Design and synthesis of peptidic partial agonists of human neuromedin U receptor 1 with enhanced serum stability. Bioorganic & medicinal chemistry letters. 2020 Sep 15;30(18):127436