Design and Synthesis of an Investigational Nonapeptide KISS1 Receptor (KISS1R) Agonist, Ac-d-Tyr-Hydroxyproline (Hyp)-Asn-Thr-Phe-azaGly-Leu-Arg(Me)-Trp-NH 2 (TAK-448), with Highly Potent Testosterone-Suppressive Activity and Excellent Water Solubility

• Published in: Journal of medicinal chemistry Vol. 59; no. 19; pp. 8804 - 8811
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 13.10.2016
• Subjects: Animals; CHO Cells; Cricetulus; Humans; Kisspeptins - administration & dosage; Kisspeptins - blood; Kisspeptins - chemistry; Kisspeptins - pharmacology; Male; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Receptors, Kisspeptin-1; Solubility; Testosterone - antagonists & inhibitors; Testosterone - blood; Testosterone - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00379

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-NH , 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.