title: Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2(TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility.
abstract: Metastin/kisspeptin is an endogenous ligand of KISS1 Receptor (KISS1R). Metastin and KISS1R are suggested to play crucial roles in regulating the secretion of gonadotropin-releasing hormone (GnRH), and continuous administration of metastin derivatives attenuated the plasma testosterone levels in male rats. Our optimization studies of metastin derivatives led to the discovery of 1 (Ac-d-Tyr-d-Trp-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH2, TAK-683), which suppressed plasma testosterone in rats at lower doses than those of leuprolide. Although 1 possessed extremely potent pharmacological activity, 20 mg/mL aqueous solution of 1 has a gel formation property. In order to improve this physicochemical property, we substituted d-Trp at position 47 with a variety of amino acids; we identified that substitution with cyclic amino acids, which could change peptide conformation, retained its potency. Especially, analogue 24 (TAK-448) with trans-4-hydroxyproline (Hyp) at position 47 showed not only superior pharmacological activity to 1 but also excellent water solubility. Furthermore, 20 mg/mL aqueous solution of 24 did not show gel formation up to 5 days.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Naoki
authors: N
authors: Nishizawa
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Yoshihiro
authors: Y
authors: Takatsu
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Satoshi
authors: S
authors: Kumano
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Atsushi
authors: A
authors: Kiba
authors: CMC Center, Takeda Pharmaceutical Company Ltd , Osaka 532-8686, Japan.
authors: Junko
authors: J
authors: Ban
authors: CMC Center, Takeda Pharmaceutical Company Ltd , Osaka 532-8686, Japan.
authors: Shunichirou
authors: S
authors: Tsutsumi
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Hisanori
authors: H
authors: Matsui
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Shin-Ichi
authors: SI
authors: Matsumoto
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Masashi
authors: M
authors: Yamaguchi
authors: CMC Center, Takeda Pharmaceutical Company Ltd , Osaka 532-8686, Japan.
authors: Yukihiro
authors: Y
authors: Ikeda
authors: CMC Center, Takeda Pharmaceutical Company Ltd , Osaka 532-8686, Japan.
authors: Masami
authors: M
authors: Kusaka
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Tetsuya
authors: T
authors: Ohtaki
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Fumio
authors: F
authors: Itoh
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd , Fujisawa 251-8555, Japan.
authors: Taiji
authors: T
authors: Asami
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D059648:Kisspeptins / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D012995:Solubility; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism
chemical_list: C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; C578072:TAK-683; D013739:Testosterone