Design, Synthesis, and Biological Evaluation of Novel Investigational Nonapeptide KISS1R Agonists with Testosterone-Suppressive Activity

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• 作者：Taiji Asami ; Naoki Nishizawa ; Hisanori Matsui ; Kimiko Nishibori ; Yoshihiro Ishibashi ; Yasuko Horikoshi ; Masaharu Nakayama ; Shin-ichi Matsumoto ; Naoki Tarui ; Masashi Yamaguchi ; Hirokazu Matsumoto ; Tetsuya Ohtaki ; Chieko Kitada
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8298-8307
• 全文大小：306K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

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鈥?4), 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-Tyr⁴⁵,d-Trp⁴⁷,azaGly⁵¹,Arg(Me)⁵³]metastin(45鈥?4) with improved serum stability compared with metastin(45鈥?4) but with decreased KISS1R agonistic activity. Amino acid replacements at positions 45鈥?7 led to an enhancement of KISS1R agonistic activity and metabolic stability. N-terminal truncation resulted in a stable nonapeptide, [d-Tyr⁴⁶,d-Pya(4)⁴⁷,azaGly⁵¹,Arg(Me)⁵³]metastin(46鈥?4), compound 26, which displayed KISS1R binding affinities comparable to metastin(45鈥?4) 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.