Synthesis and structure-activity relationships of 8-substituted-2-aryl-5-alkylaminoquinolines: Potent, orally active corticotropin-releasing factor-1 receptor antagonists

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• 作者：Kunitoshi Takeda^a ; ^{k5-takeda@hhc.eisai.co.jp} ; Taro Terauchi^a ; Minako Hashizume^a ; Kohdoh Shikata^b ; Ryota Taguchi^b ; Kaoru Murata-Tai^c ; Masae Fujisawa^d ; Yoshinori Takahashi^a ; Kogyoku Shin^a ; Mitsuhiro Ino^b ; Hisashi Shibata^b ; Masahiro Yonaga^a
• 关键词：Corticotropin-releasing factor ; Pharmacophore ; Solubility ; Structure&ndash ; activity relationships ; Depression
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2012
• 出版时间：15 November, 2012
• 年：2012
• 卷：20
• 期：22
• 页码：6559-6578
• 全文大小：1344 K

文摘

We previously reported a series of 8-methyl-2-aryl-5-alkylaminoquinolines as a novel class of corticotropin-releasing factor-1 (CRF₁) receptor antagonists. A critical issue encountered for this series of compounds was low aqueous solubility at physiological pH (pH 7.4). To address this issue, derivatization at key sites (R², R³, R⁵, R^5¡ä, and R⁸) was performed and the relationships between structure and solubility were examined. As a result, it was revealed that introduction of a methoxy substituent at the C₈ position had a positive impact on the solubility of the derivatives. Consequently, through in vivo and in vitro biological studies, compound 21d was identified as a potent, orally active CRF₁ receptor antagonist with improved physicochemical properties.