Niida Ayumu, Kanematsu-Yamaki Yoko, Asakawa Tomoko, Ishimura Yoshimasa, Fujita Hisashi, Matsumiya Kouta, Nishizawa Naoki, Adachi Yusuke, Mochida Taisuke, Tsuchimori Kazue, Yoneyama-Hirozane Mariko, Sakamoto Junichi, Hirabayashi Hideki, Fukui Hideo, Takekawa Shiro, Asami Taiji
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa 251-8555, Japan.
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa 251-8555, Japan.
Bioorg Med Chem. 2018 Feb 1;26(3):566-572. doi: 10.1016/j.bmc.2017.12.014. Epub 2017 Dec 8.
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,Iva,Pya(4),Cha,γMeLeu,Lys,Aib]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) and longer time at maximum concentration (T). Compounds 5 and 10, modified with 20 kDa PEG at the N-terminus and eicosanedioic acid at the Lys 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 and long T, 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）激动作用是一种重要的食欲抑制信号，也是抗肥胖药物研发的一个靶点。最近，我们合成了一种短长度的Y2R激动剂PYY - 1119（4 - 咪唑羰基 - [d - Hyp，Iva，Pya(4)，Cha，γMeLeu，Lys，Aib]PYY(23 - 36)，1）作为抗肥胖药物候选物。化合物1在饮食诱导肥胖（DIO）小鼠中引起显著体重减轻；然而，1在比给予DIO小鼠的最小有效剂量更低的剂量下也会在犬中引起严重呕吐。皮下给药后1的快速吸收导致了严重呕吐。合成了1的聚乙二醇（PEG）和烷基修饰衍生物，以开发具有改善药代动力学特征的Y2R激动剂，即较低的最大血浆浓度（C）和较长的最大浓度时间（T）。分别在1的N端用20 kDa PEG修饰以及在Lys侧链用二十烷二酸修饰的化合物5和10，显示出高Y2R结合亲和力，并且在对DIO小鼠每日给药一次时诱导显著体重减轻。与1相比，化合物5和10具有相对较低的C和较长的T，在犬中部分减轻了呕吐。这些结果表明，优化Y2R激动剂的药代动力学性质是减轻Y2R激动作用诱导的呕吐的有效策略。
