title: Retinoid X receptor-antagonistic diazepinylbenzoic acids.
abstract: 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-Dimethyl-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).
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ebisawa
authors.forename: H
authors.initials: H
authors.lastname: Umemiya
authors.forename: K
authors.initials: K
authors.lastname: Ohta
authors.forename: H
authors.initials: H
authors.lastname: Fukasawa
authors.forename: E
authors.initials: E
authors.lastname: Kawachi
authors.forename: G
authors.initials: G
authors.lastname: Christoffel
authors.forename: H
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: M
authors.initials: M
authors.lastname: Tsuji
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: K
authors.initials: K
authors.lastname: Shudo
authors.forename: H
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D015533:Transcriptional Activation
chemical_list: D001381:Azepines; D001565:Benzoates; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors