Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions.
Several 2-(arylamino)pyrimidine-5-carboxylic acids were designed as novel retinoid X receptor (RXR) antagonists. Compound 6a or 6b alone did not exhibit differentiation-inducing activity toward HL-60 cells and did not affect the activity of a retinoic acid receptor (RAR) agonist, Am80, but did inhibit the synergistic activity of an RXR agonist, PA024 (3), in the presence of Am80. The activity of 6 was ascribed to selective antagonism at the RXR site of RXR-RAR heterodimers.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Bitoku
B
Takahashi
Kiminori
K
Ohta
Emiko
E
Kawachi
Hiroshi
H
Fukasawa
Yuichi
Y
Hashimoto
Hiroyuki
H
Kagechika
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003864:Depression, Chemical; D019281:Dimerization; D018922:HL-60 Cells; D006801:Humans; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D001565:Benzoates; D002264:Carboxylic Acids; C000608768:PA024 compound; D011743:Pyrimidines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C061133:tamibarotene; D015081:2-Naphthylamine