Novel retinoid X receptor antagonists: Specific inhibition of retinoid synergism in RXR-RAR heterodimer actions

被引：75

作者：

Takahashi, B

Ohta, K

Kawachi, E

Fukasawa, H

Hashimoto, Y

Kagechika, H

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[2] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 16期

关键词：

D O I：

10.1021/jm0255320

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

收藏

页码：3327 / 3330

页数：4

相关论文

共 23 条

[1] Enhancement of HL-60 differentiation by a new class of retinoids with selective activity on retinoid X receptor [J].

Apfel, CM ;

Kamber, M ;

Klaus, M ;

Mohr, P ;

Keidel, S ;

LeMotte, PK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (51) :30765-30772

[2] The rexinoid LG100754 is a novel RXR:PPARγ agonist and decreases glucose levels in vivo [J].

Cesario, RM ;

Klausing, K ;

Razzaghi, H ;

Crombie, D ;

Rungta, D ;

Heyman, RA ;

Lala, DS .

MOLECULAR ENDOCRINOLOGY, 2001, 15 (08) :1360-1369

[3] A decade of molecular biology of retinoic acid receptors [J].

Chambon, P .

FASEB JOURNAL, 1996, 10 (09) :940-954

[4] Two distinct actions of retinoid-receptor ligands [J].

Chen, JY ;

Clifford, J ;

Zusi, C ;

Starrett, J ;

Tortolani, D ;

Ostrowski, J ;

Reczek, PR ;

Chambon, P ;

Gronemeyer, H .

NATURE, 1996, 382 (6594) :819-822

[5]

Ebisawa M, 1999, CHEM PHARM BULL, V47, P1778

[6] 9-CIS RETINOIC ACID IS A HIGH-AFFINITY LIGAND FOR THE RETINOID-X RECEPTOR [J].

HEYMAN, RA ;

MANGELSDORF, DJ ;

DYCK, JA ;

STEIN, RB ;

EICHELE, G ;

EVANS, RM ;

THALLER, C .

CELL, 1992, 68 (02) :397-406

[7]

KAGECHIKA H, 2000, IDRUGS, V3, P73

[8] Identification of the first retinoid X receptor homodimer antagonist [J].

Koch, SSC ;

Dardashti, LJ ;

Hebert, JJ ;

White, SK ;

Croston, GE ;

Flatten, KS ;

Heyman, RA ;

Nadzan, AM .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (17) :3229-3234

[9] Activation of specific RXR heterodimers by an antagonist of RXR homodimers [J].

Lala, DS ;

Mukherjee, R ;

Schulman, IG ;

Koch, SSC ;

Dardashti, LJ ;

Nadzan, AM ;

Croston, GE ;

Evans, RM ;

Heyman, RA .

NATURE, 1996, 383 (6599) :450-453

[10]

LAUDET V, 2000, NUCL RECEPTOR FACTSB, P248