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Retinoid X Receptor-Antagonistic Diazepinylbenzoic Acids.

1999; Pharmaceutical Society of Japan; Volume: 47; Issue: 12 Linguagem: Inglês

10.1248/cpb.47.1778

1347-5223

Masayuki Ebisawa, Hiroki Umemiya, Kiminori Ohta, Hiroshi Fukasawa, Emiko Kawachi, Ghislaine CHRISTOFFEL, Hinrich Gronemeyer, Motonori Tsuji, Yuichi Hashimoto, Koichi SHUDO, Hiroyuki Kagechika,

Nuclear Receptors and Signaling

Several dibenzodiazepine derivatives were identified as novel retinoid X receptor (RXR) antagonists on the basis of inhibitory activity on retinoid-induced cell differentiation of human promyelocytic leukemia cells HL-60 and transactivation assay using retinoic acid receptors (RARs) and RXRs in COS-1 cells. 4-(5H-2, 3-(2, 5-Di-methyl-2, 5-hexano)-5-n-propyldibenzo[b, e][1, 4]diazepin-11-yl)benzoic acid (HX603, 6c) is an N-n-propyl derivative of an RXR pan-agonist HX600 (6a), and exhibited RXR-selective antagonistic activity. Similar RXR-antagonistic activities were observed with 4-(5H-2, 3-(2, 5-dimethyl-2, 5-hexano)-5-methyl-8-nitrodibenzo[b, e][1, 4]diazepin-11-yl)benzoic acid (HX531, 7a) and 4-(5H-10, 11-dihydro-5, 10-dimethyl-2, 3-(2, 5-dimethyl-2, 5-hexano)-dibenzo[b, e][1, 4]diazepin-11-yl)benzoic acid (HX711, 8b), which also inhibited transactivation of RARs induced by an RAR agonist, Am80. These compounds inhibited HL-60 cell differentiation induced by the combination of a low concentration of the retinoid agonist Am80 with an RXR agonist (a retinoid synergist, HX600). These results indicated that HX603 (6c), and the related RXR antagonists inhibit the activation of RAR-RXR heterodimers as well as RXR homodimers, which is a distinct characteristic different from that of the known RXR antagonist, LG100754 (9).