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-Hyp²⁴,Iva²⁵,Pya(4)²⁶,Cha^27,36,γMeLeu²⁸,Lys³⁰,Aib³¹]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 Lys³⁰ 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.

神经肽Y2受体（Y2R）激动是重要的厌食信号，也是抗肥胖药发现的目标。最近，我们合成的短长度Y2R激动剂，PYY-1119（4- imidazolecarbonyl- [ d -Hyp ²⁴，IVA ²⁵，PYA（4）²⁶，查^27,36，γMeLeu ²⁸，赖氨酸³⁰，Aib取代³¹ ] PYY（ 23–36），1）作为抗肥胖药的候选药物。化合物1在饮食诱发的肥胖（DIO）小鼠中引起明显的体重减轻；然而，1还以低于DIO小鼠最低有效剂量的剂量在狗中引起严重呕吐。快速吸收1皮下给药后引起严重呕吐。合成了1的聚乙二醇（PEG）和烷基修饰的衍生物，以开发具有改善的药代动力学特征的Y2R激动剂，即，较低的最大血浆浓度（C _max）和在最大浓度下的时间较长（T _max）。分别在N末端的20 kDa PEG和1的Lys ³⁰侧链的二十碳二酸修饰的化合物5和10在向DIO小鼠每天给药后显示出很高的Y2R结合亲和力，并导致体重显着降低。具有较低C的化合物5和10_最大和长T_最大，部分衰减的呕吐在狗相比1。这些结果表明，优化Y2R激动剂的药代动力学特性是减轻由Y2R激动剂诱导的呕吐的有效策略。