Retinoic acid receptor antagonist

Scheme 2.2-16. Synthesis of retinoic acid receptor antagonist.

Johnson AT, Wang L, Standeven AM et al (1999) Synthesis and biological activity of high-affinity retinoic acid receptor antagonists. Bioorg Med Chem 7 1321-1338... 

Therapeutic uses of retinoic acid receptor antagonists and inverse agonists... 

Yoshimura H, Nagai M, Hibi S, Kikuchi K, Abe S, Hida T, Higashi S, Hishinuma I, Yamanaka T (1995) A novel type of retinoic acid receptor antagonist synthesis and structure-activity relationships of heterocyclic ring-containing benzoic acid derivatives. J Med Chem 38 3163-3173... 

Retinoic acid receptor a (RARa) antagonist, 55% inhibition at 20 pM... 

Chromens and their derivatives are an important class of compounds possessing antiestrogenic, [165] potassium channel agonist, hypotensive [166], vasodilator, antihypertensive, p-adrenolytic [167] and antimicrobial activity [168]. Moreover, some derivatives show high antagonistic affinity for the retinoic acid receptor [169]. 

CYP26 expression in normal human tracheobronchial epithelial cells was compared with that in human lung carcinoma cell lines (Kim et al. 2000). CYP26 mRNA could be induced by the retinoic acid receptor-selective retinoid 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid but not by the retinoid X receptor-selective retinoid SRI 1217 or the anti-activator-protein 1-selective retinoid SRI 1302. Retinoic acid receptor a-, P, and y-selective retinoids were able to induce CYP26 this induction was inhibited by the retinoic acid receptora-selective antagonist Ro41-5253. The induction of CYP26 correlated with increased biotransformation of retinoic acid into 18-hydroxy-, 4-OXO-, and 4-hydroxy-retinoic acid. 

Consequently, Endo et al. prepared and screened a series of carborane-based retinoic acid receptor agonists [278-280] and antagonists [281,282] having both amide and amine cores, containing carborane substituents at the 3 and 4 positions of the central aryl group. More recently, syntheses of novel carboranyl testosterone (Figure 25) [283-285] and cholesterol (Figure 15) [203] mimics were reported. 

Keidel S, LeMotte P, Apfel C (1994) Different agonist- and antagonist-induced conformational changes in retinoic acid receptors analyzed by protease mapping. Mol Cell Biol 14 287-298... 

Eyrolles L, Kagechika H, Kawachi E, Fukasawa H, lijima T, Matsushima Y, Hashimoto Y, Shudo K (1994) Retinobenzoic acids. 6. Retinoid antagonists with a heterocyclic ring. J Med Chem 37 1508-1517 Crettaz M, Baron A, Siegenthaler G, Hunziker W (1990) Ligand specificities of recombinant retinoic acid receptors RAR a and RAR p. Biochem J 272 391-397... 

Apfel C, Bauer F, Crettaz M, Fomi L, Kamber M, Kaufmann F, LeMotte P, Pirson W, Klaus M (1992) A retinoic acid receptor a antagonist selectively counteracts retinoic acid effects. Proc Natl Acad Sci USA 89 7129-7133... 

Klein ES, Pino ME, Johnson AT, Davies PJA, Nagpal S, Thacher SM, Krasinski G, Chandraratna RAS (1996) Identification and functional separation of retinoic acid receptor neutral antagonists and inverse agonists. J Biol Chem 111 22 692-22 696... 

Johnson AT, Klein ES, Gillett SJ, Wang L, Song TK, Pino ME, Chandraratna RAS (1995) Synthesis and characterization of a highly potent and effective antagonist of retinoic acid receptors. J Med Chem 38 4764-4767... 

Ueno H, Kizaki M, Matsushita H, Muto A, Yamato K, Nishihara T, Hida T, Yoshimura H, Koeffler HP, Ikeda Y (1998) A novel retinoic acid receptor (RAR)-selective antagonist inhibits differentiation and apoptosis of HL-60 cells Implications of RARa-mediated signals in myeloid leukemic cells. LeukRes 22 517-525... 

Teng M, Duong TT, Johnson AT, Klein ES, Wang L, Khalifa B, Chandraratna RAS (1997) Identification of highly potent retinoic acid receptor a-selective antagonists. J Med Chem 40 2445-2451... 

Eckhardt K, Schmitt G (1994) A retinoic acid receptor a antagonist counteracts retinoid teratogenicity in vitro and reduced incidence and/or severity of malformations in vivo. Toxicol Lett 70 299-308... 

Table 16. Retinoic Acids, Vitamin D, and Type II Receptor Agonists and Antagonists...

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