Syntheses and structure-activity relationships of novel retinoid X receptor agonists.
As part of our studies to develop novel retinoids with increased affinity and selectivity for the retinoid X receptor (RXR) subfamily, we have designed and synthesized a series of (E,E,E)-7-(1,2,3, 4-tetrahydroquinolin-6-yl)-7-alkyl-6-fluoro-3-methylhepta-2, 4, 6-trienoic acid derivatives. These tetrahydroquinolines, generated by introducing a polar N atom into the hydrophobic part of the retinoid skeleton, showed high binding affinity to RXRs. Addition of fluorine at the 6-position of the 2,4,6-trienoic acid moiety afforded compounds which elicit potent and selective transactivation of the RXRs. Compound 14b (ER-35794), which possesses an ethyl substituent at the 7-position and fluorine at the 6-position of the triene moiety, is one of the most potent and selective RXR agonists reported to date.
Hibi
S
S
Tsukuba Basic Research Laboratories, Eisai Co., Ltd., 1-3, Tokodai 5-chome, Tsukuba-shi, Ibaraki, 300-26, Japan. s1-hibi@eisai.co.jp
Kikuchi
K
K
Yoshimura
H
H
Nagai
M
M
Tai
K
K
Hida
T
T
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*
D015363:Quinolones; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin