Antiobesity and emetic effects of a short-length peptide YY analog and its PEGylated and alkylated derivatives. Issue 3 (1st February 2018)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 3(2018)
• Page Start: 566
• Page End: 572
• Publication Date: 2018-02-01
• Subjects: Ac acetyl -- Aib 2-aminoisobutyric acid -- tBu tert-butyl -- Cha 3-cyclohexylalanine -- CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate -- DIO diet-induced obese -- DIPCDI N, N′-diisopropylcarbodiimide -- DMF N, N-dimethylformamide -- DMSO dimethyl sulfoxide -- EDTA ethylenediaminetetraacetic acid -- Fmoc 9-fluorenylmethoxycarbonyl -- HOAt 1-hydroxy-7-azabenzotriazole -- HOBt 1-hydroxybenzotriazole -- HPLC high-performance liquid chromatography -- Hyp trans-4-hydroxyproline -- Im(4)CO 4-imidazolecarbonyl -- Iva isovaline [(S)-2-amino-2-methylbutanoic acid)] -- LC/MS/MS liquid chromatography–tandem mass spectrometry -- MALDI-TOF matrix-assisted laser desorption/ionization time-of-flight -- γMeLeu γ-methylleucine (2-amino-4, 4-dimethylpentanoic acid) -- MS mass spectrometry -- NPY neuropeptide Y -- Pbf 2, 2, 4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl -- PCR polymerase chain reaction -- PEG polyethylene glycol -- PEG(2) O-(3-aminopropyl)-O′-(N-diglycolyl-3-aminopropyl)diethyleneglycol -- 4-Pic 4-piperidinecarbonyl -- PMSF phenylmethylsulfonyl fluoride -- Pya(4) 3-(4-pyridyl)alanine -- PYY peptide YY -- RP reversed-phase -- TFA trifluoroacetic acid -- Tra tranexamic acid -- Trt triphenylmethyl (trityl); Peptide YY -- Neuropeptide Y2 receptor agonist -- Antiobesity -- PEGylation -- Alkylation -- Emesis; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.014
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 (Cmax ) and longer time at maximum concentration (Tmax ). 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 Cmax and long Tmax, 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.