872720-12-2Relevant articles and documents
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
Nishizawa, Naoki,Takatsu, Yoshihiro,Kumano, Satoshi,Kiba, Atsushi,Ban, Junko,Tsutsumi, Shunichirou,Matsui, Hisanori,Matsumoto, Shin-Ichi,Yamaguchi, Masashi,Ikeda, Yukihiro,Kusaka, Masami,Ohtaki, Tetsuya,Itoh, Fumio,Asami, Taiji
, p. 8804 - 8811 (2016)
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.
