title: Physicochemically and pharmacokinetically stable nonapeptide KISS1 receptor agonists with highly potent testosterone-suppressive activity.
abstract: Modifications of metastin(45-54) produced peptide analogues with higher metabolic stability than metastin(45-54). N-terminally truncated nonapeptide 4 ([D-Tyr46,D-Pya(4)47,azaGly51,Arg(Me)53]metastin(46-54)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn48 and Ser49; substitution of Ser49 with Thr49 reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54) (14) showed 2-fold greater [Ca2+]i-mobilizing activity than metastin(45-54) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[D-Tyr46,D-Trp47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54)). With continuous administration, 22 possessed 10-50-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic-pituitary-gonadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd. , Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Taiji
authors.initials: T
authors.lastname: Asami
authors.forename: Naoki
authors.initials: N
authors.lastname: Nishizawa
authors.forename: Hisanori
authors.initials: H
authors.lastname: Matsui
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takatsu
authors.forename: Atsuko
authors.initials: A
authors.lastname: Suzuki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kiba
authors.forename: Michiko
authors.initials: M
authors.lastname: Terada
authors.forename: Kimiko
authors.initials: K
authors.lastname: Nishibori
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Junko
authors.initials: J
authors.lastname: Ban
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Kusaka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ohtaki
authors.forename: Chieko
authors.initials: C
authors.lastname: Kitada
mesh_terms: D000818:Animals; D016466:CHO Cells; D002627:Chemistry, Physical; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D059648:Kisspeptins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008968:Molecular Conformation; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000074502:Receptors, Kisspeptin-1; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C118688:KISS1R protein, human; D059648:Kisspeptins; D009842:Oligopeptides; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D013739:Testosterone