Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry
5 years ago

Highly potent antiobesity effect of a short-length peptide YY analog in mice

Highly potent antiobesity effect of a short-length peptide YY analog in mice
Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[D-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23–36) (4), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans-4-hydroxy-D-proline (D-Hyp)24, isovaline (Iva)25, and γ-methylleucine (γMeLeu)28, not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[D-Hyp24,Iva25,Pya(4)26,Cha27,36,γMeLeu28,Lys30,Aib31]PYY(23–36) (31, PYY-1119) at a dose of 0.03 mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction.

Publisher URL: www.sciencedirect.com/science

DOI: S0968089617314463

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