Compound 1 exhibits potent binding inhibition activity against a corticotropin-releasing factor 1 (CRF₁) receptor (IC₅₀ = 9.5 nM) and in vitro antagonistic activity (IC₅₀ = 88 nM) but is rapidly metabolized by human hepatic microsomes (182 μL/min/mg). Here we identified metabolically stable compounds with potent CRF binding inhibitory activity. Structure–activity relationship (SAR) studies considering in vitro metabolic stability revealed that 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzimidazole 24d was more stable in human microsomes (87 μL/min/mg) than compound 1. Compound 24d demonstrated potent CRF binding inhibitory activity (IC₅₀ = 4.1 nM), in vitro antagonistic activity (IC₅₀ = 44 nM), and slow dissociation from the CRF₁ receptor. Orally administered compound 24d (6–24 μmol/kg) showed ex vivo CRF₁ receptor binding in the rat pituitary, olfactory bulb, and frontal cortex and suppressed stress-induced adrenocorticotropic hormone (ACTH) secretion. In this report, we discuss SAR studies on the metabolic stability as well as CRF binding inhibitory activity of the benzimidazole series as CRF₁ receptor antagonists and the pharmacological profiles of compound 24d.

化合物1对促肾上腺皮质激素释放因子1（CRF ₁）受体（IC ₅₀  = 9.5 nM）表现出有效的结合抑制活性，并在体外具有拮抗活性（IC ₅₀  = 88 nM），但会被人肝微粒体迅速代谢（182μL/分钟/毫克）。在这里，我们确定了具有有效CRF结合抑制活性的代谢稳定化合物。结构-活性关系（SAR）考虑在体外代谢稳定性研究表明，4-氯-2-（2,4-二氯-6-甲基苯氧基）-1-甲基-7-（戊烷-3-基）-1- ħ -苯并咪唑24d在人微粒体内（87μL/ min / mg）比化合物1更稳定。复合24d证实了有效的CRF结合抑制活性（IC ₅₀  = 4.1 nM），体外拮抗活性（IC ₅₀  = 44 nM）和与CRF ₁受体的缓慢解离。口服给药的化合物24d（6-24μmol/ kg）在大鼠垂体，嗅球和额叶皮层中显示离体CRF ₁受体结合，并抑制了应激诱导的促肾上腺皮质激素（ACTH）分泌。在本报告中，我们讨论了关于苯并咪唑系列作为CRF ₁受体拮抗剂的代谢稳定性以及CRF结合抑制活性的SAR研究，以及化合物24d的药理作用。