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

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, R5′, 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.