Discovery of a Human Neuromedin U Receptor 1-Selective Hexapeptide Agonist with Enhanced Serum Stability

  • J Med Chem. 2017 Jun 22;60(12):5228-5234. doi: 10.1021/acs.jmedchem.7b00694.
Kentaro Takayama  1 ,  Kenji Mori  2 ,  Akiko Tanaka  3 ,  Erina Nomura  1 ,  Yuko Sohma  1 ,  Miwa Mori  2 ,  Akihiro Taguchi  1 ,  Atsuhiko Taniguchi  1 ,  Toshiyasu Sakane  4 ,  Akira Yamamoto  3 ,  Naoto Minamino  5 ,  Mikiya Miyazato  2 ,  Kenji Kangawa  2 ,  Yoshio Hayashi  1
Affiliations
  • 1. Department of Medicinal Chemistry, Tokyo University of Pharmacy and Life Sciences , 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • 2. Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
  • 3. Department of Biopharmaceutics, Kyoto Pharmaceutical University , 5 Misasaginakauchi-cho, Yamashina, Kyoto 607-8414, Japan.
  • 4. Laboratory of Pharmaceutical Technology, Kobe Pharmaceutical University , 4-19-1 Motoyamakitamachi, Higashinada, Kobe, Hyogo 658-8558, Japan.
  • 5. Omics Research Center, National Cerebral and Cardiovascular Center , 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
PMID: 28548497 DOI: 10.1021/acs.jmedchem.7b00694
Abstract

Neuromedin U (NMU) activates two NMU receptors (NMUR1 and NMUR2) and is a useful antiobesity drug lead. We report discovery of a hexapeptide agonist, 2-thienylacetyl-Trp1-Phe(4-F)2-Arg3-Pro4-Arg5-Asn6-NH2 (4). However, the NMUR1 selectivity and serum stability of this agonist were unsatisfactory. Through a structure-activity relationship study focused on residue 2 of agonist 4, serum stability, and pharmacokinetic properties, we report here the discovery of a novel NMUR1 selective hexapeptide agonist 7b that suppresses body weight gain in mice.

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