title: Design, synthesis, and biological evaluation of novel investigational nonapeptide KISS1R agonists with testosterone-suppressive activity.
abstract: Metastin/kisspeptin is a 54 amino acid peptide ligand of the KISS1R receptor and is a critical regulator of GnRH secretion. The N-terminally truncated peptide, metastin(45-54), possesses a 10-fold higher receptor-binding affinity than full-length metastin and agonistic KISS1R activity but is rapidly inactivated in rodent plasma. We have developed a decapeptide analog [D-Tyr(45),D-Trp(47),azaGly(51),Arg(Me)(53)]metastin(45-54) with improved serum stability compared with metastin(45-54) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45-47 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [D-Tyr(46),D-Pya(4)(47),azaGly(51),Arg(Me)(53)]metastin(46-54), compound 26, which displayed KISS1R binding affinities comparable to metastin(45-54) and had improved serum stability. Compound 26 reduced plasma testosterone in male rats and is the first short-length metastin analog to possess testosterone suppressive activities. Compound 26 has led to the elucidation of investigational analogs TAK-683 and TAK-448, both of which have undergone clinical evaluation for hormone-dependent diseases such as prostate cancer.
authors.affiliation: Pharmaceutical Research Division, Shonan Research Center, Takeda Pharmaceutical Company Ltd , 2-26-1, Muraoka-Higashi 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: Kimiko
authors.initials: K
authors.lastname: Nishibori
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishibashi
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakayama
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tarui
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsumoto
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; D003412:Cricetulus; D015195:Drug Design; D015507:Drugs, Investigational / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D059648:Kisspeptins / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D015507:Drugs, Investigational; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D013739:Testosterone