Takeda Pharmaceutical Company Ltd. , 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.
J Med Chem. 2016 Mar 24;59(6):2551-66. doi: 10.1021/acs.jmedchem.5b01715. Epub 2016 Mar 7.
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-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-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.
设计、合成并评价了一种新型 CRF1 受体拮抗剂，该拮抗剂的苯并咪唑衍生物通过单原子连接基团与柔性芳基键合。我们期望结构多样性能够超出已报道的 CRF1 受体拮抗剂。在构效关系研究中，4-氯-N(2)-(4-氯-2-甲氧基-6-甲基苯基)-1-甲基-N(7)，N(7)-二丙基-1H-苯并咪唑-2,7-二胺 29g 对人 CRF1 受体具有最强的结合活性和拮抗活性（IC50 分别为 9.5 和 88 nM），在 30 μM 时没有细胞毒性问题。在离体试验中，化合物 29g 在脑内具有很强的 CRF1 受体结合活性，并且在口服给予小鼠 138 μmol/kg 后，也能抑制应激诱导的下丘脑-垂体-肾上腺 (HPA) 轴的激活。因此，新设计的苯并咪唑 29g 表现出体内 CRF1 受体拮抗活性和良好的脑穿透性，表明它是 CRF1 受体拮抗剂药物发现研究的有前途的先导化合物。
