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

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-Trp 1 -Phe(4-F) 2 -Arg 3 -Pro 4 -Arg 5 -Asn 6 -NH 2 ( 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.