Physicochemically and Pharmacokinetically Stable Nonapeptide KISS1 Receptor Agonists with Highly Potent Testosterone-Suppressive Activity

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• 作者：Taiji Asami ; Naoki Nishizawa ; Hisanori Matsui ; Yoshihiro Takatsu ; Atsuko Suzuki ; Atsushi Kiba ; Michiko Terada ; Kimiko Nishibori ; Masaharu Nakayama ; Junko Ban ; Shin-ichi Matsumoto ; Naoki Tarui ; Yukihiro Ikeda ; Masashi Yamaguchi ; Masami Kusaka ; Tetsuya Ohtaki ; Chieko Kitada
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6105-6115
• 全文大小：300K
• ISSN：1520-4804

文摘

Modifications of metastin(45鈥?4) produced peptide analogues with higher metabolic stability than metastin(45鈥?4). N-terminally truncated nonapeptide 4 ([d-Tyr⁴⁶,d-Pya(4)⁴⁷,azaGly⁵¹,Arg(Me)⁵³]metastin(46鈥?4)) is a representative compound with both potent agonistic activity and metabolic stability. Although 4 had more potent testosterone-suppressant activity than metastin, it possessed physicochemical instability at pH 7 and insufficient in vivo activity. Instability at pH 7 was dependent upon Asn⁴⁸ and Ser⁴⁹; substitution of Ser⁴⁹ with Thr⁴⁹ reduced this instability and maintained KISS1 receptor agonistic activity. Furthermore, [d-Tyr⁴⁶,d-Trp⁴⁷,Thr⁴⁹,azaGly⁵¹,Arg(Me)⁵³,Trp⁵⁴]metastin(46鈥?4) (14) showed 2-fold greater [Ca²⁺]_i-mobilizing activity than metastin(45鈥?4) and an apparent increase in physicochemical stability. N-terminal acetylation of 14 resulted in the most potent analogue, 22 (Ac-[d-Tyr⁴⁶,d-Trp⁴⁷,Thr⁴⁹,azaGly⁵¹,Arg(Me)⁵³,Trp⁵⁴]metastin(46鈥?4)). With continuous administration, 22 possessed 10鈥?0-fold more potent testosterone-suppressive activity in rats than 4. These results suggested that a controlled release of short-length KISS1 receptor agonists can suppress the hypothalamic鈥損ituitary鈥揼onadal axis and reduce testosterone levels. Compound 22 was selected for further preclinical evaluation for hormone-dependent diseases.