Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives

Abstract Neuropeptide Y2 receptor (Y2R) agonism is an important anorectic signal and a target of antiobesity drug discovery. Recently, we synthesized a short-length Y2R agonist, PYY-1119 (4-imidazolecarbonyl-[ d -Hyp 24 ,Iva 25 ,Pya(4) 26 ,Cha 27,36 ,γMeLeu 28 ,Lys 30 ,Aib 31 ]PYY(23–36), 1 ) as an antiobesity drug candidate. Compound 1 induced marked body weight loss in diet-induced obese (DIO) mice; however, 1 also induced severe vomiting in dogs at a lower dose than the minimum effective dose administered to DIO mice. The rapid absorption of 1 after subcutaneous administration caused the severe vomiting. Polyethylene glycol (PEG)- and alkyl-modified derivatives of 1 were synthesized to develop Y2R agonists with improved pharmacokinetic profiles, i.e., lower maximum plasma concentration (C max ) and longer time at maximum concentration (T max ). Compounds 5 and 10 , modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys 30 side chain of 1 , respectively, showed high Y2R binding affinity and induced significant body weight reduction upon once-daily administration to DIO mice. Compounds 5 and 10 , with their relatively low C max and long T max , partially attenuated emesis in dogs compared with 1 . These results indicate that optimization of pharmacokinetic properties of Y2R agonists is an effective strategy to alleviate emesis induced by Y2R agonism.