1. Synthesis and structure–activity relationships of 8-substituted-2-aryl-5-alkylaminoquinolines: Potent, orally active corticotropin-releasing factor-1 receptor antagonists
- Author
-
Yoshinori Takahashi, Hisashi Shibata, Kaoru Murata-Tai, Kohdoh Shikata, Masahiro Yonaga, Masae Fujisawa, Taro Terauchi, Kogyoku Shin, Minako Hashizume, Ryota Taguchi, Kunitoshi Takeda, and Mitsuhiro Ino
- Subjects
medicine.drug_class ,Stereochemistry ,Clinical Biochemistry ,Substituent ,Administration, Oral ,Pharmaceutical Science ,Receptors, Corticotropin-Releasing Hormone ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Solubility ,Receptor ,Molecular Biology ,Mice, Inbred BALB C ,Behavior, Animal ,Chemistry ,Aryl ,Organic Chemistry ,Hydrogen-Ion Concentration ,Receptor antagonist ,Rats ,Drug Design ,Aminoquinolines ,Molecular Medicine ,Pharmacophore ,Half-Life - Abstract
We previously reported a series of 8-methyl-2-aryl-5-alkylaminoquinolines as a novel class of corticotropin-releasing factor-1 (CRF(1)) 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 (R(2), R(3), R(5), R(5'), and R(8)) 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 C(8) 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 CRF(1) receptor antagonist with improved physicochemical properties.
- Published
- 2012
- Full Text
- View/download PDF