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 (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.
Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd, 5-1-3 Tokodai, Tsukuba-shi, Ibaraki, Japan. k5-takeda@hhc.eisai.co.jp
Kunitoshi
K
Takeda
Taro
T
Terauchi
Minako
M
Hashizume
Kohdoh
K
Shikata
Ryota
R
Taguchi
Kaoru
K
Murata-Tai
Masae
M
Fujisawa
Yoshinori
Y
Takahashi
Kogyoku
K
Shin
Mitsuhiro
M
Ino
Hisashi
H
Shibata
Masahiro
M
Yonaga
D000284:Administration, Oral; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015195:Drug Design; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
C578969:2-(2,6-dimethoxy-4-(methoxymethyl)phenyl)-N,N-diethyl-8-methoxy-3-methylquinolin-5-amine; D000634:Aminoquinolines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1