Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists

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• 作者：Michiyo Mochizuki ; Masakuni Kori ; Katsumi Kobayashi ; Takahiko Yano ; Yuu Sako ; Maiko Tanaka ; Naoyuki Kanzaki ; Albert C. Gyorkos ; Christopher P. Corrette ; Suk Young Cho ; Scott A. Pratt ; Kazuyoshi Aso
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2551-2566
• 全文大小：589K
• ISSN：1520-4804

文摘

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF₁) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF₁ receptor antagonists. In a structure–activity relationship study, 4-chloro-N²-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N⁷,N⁷-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF₁ receptor and the antagonistic activity (IC₅₀ = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF₁ receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus–pituitary–adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF₁ receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF₁ receptor antagonist drug discovery research.