Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.

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Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H

Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers.

J Med Chem. 1997 Dec 19;40(26):4222-34.

PubMed ID
9435893 [ View in PubMed
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Abstract

In human HL-60 promyelocytic leukemia cells, diazepinylbenzoic acid derivatives can exhibit either antagonistic or synergistic effects on the differentiation-inducing activities of natural or synthetic retinoids, the activity depending largely on the nature of the substituents on the diazepine ring. Thus, a benzolog of the retinoid antagonist LE135 (6), 4-(13H-10,11,12,13-tetrahydro-10, 10,13,13,15-pentamethyldinaphtho[2,3-b][1,2-e]diazepin-7-yl) benzoic acid (LE540, 17), exhibits a 1 order of magnitude higher antagonistic potential than the parental LE135 (6). In contrast, 4-[5H-2,3-(2,5-dimethyl-2,5-hexano)-5-methyldibenzo[b,e] [1,4]diazepin-11-yl]-benzoic acid (HX600, 7), a structural isomer of the antagonistic LE135 (6), enhanced HL-60 cell differentiation induced by RAR agonists, such as Am80 (2). This synergistic effect was further increased for a thiazepine, HX630 (29), and an azepine derivative, HX640 (30); both synergized with Am80 (2) more potently than HX600 (7). Notably, the negative and positive effects of the azepine derivatives on retinoidal actions can be related to their RAR-antagonistic and RXR-agonistic properties, respectively, in the context of the RAR-RXR heterodimer.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BexaroteneRetinoic acid receptor RXR-alphaKi (nM)16N/AN/ADetails
BexaroteneRetinoic acid receptor RXR-betaKi (nM)5.9N/AN/ADetails
BexaroteneRetinoic acid receptor RXR-gammaKi (nM)8.3N/AN/ADetails
TamibaroteneRetinoic acid receptor alphaKi (nM)6.5N/AN/ADetails
TamibaroteneRetinoic acid receptor betaKi (nM)30N/AN/ADetails
TretinoinRetinoic acid receptor alphaKi (nM)3.3N/AN/ADetails
TretinoinRetinoic acid receptor betaKi (nM)4.1N/AN/ADetails
TretinoinRetinoic acid receptor gammaKi (nM)0.04N/AN/ADetails
TretinoinRetinoic acid receptor gammaKi (nM)1N/AN/ADetails
TretinoinRetinoic acid receptor RXR-alphaKi (nM)330N/AN/ADetails
TretinoinRetinoic acid receptor RXR-alphaKi (nM)12N/AN/ADetails
TretinoinRetinoic acid receptor RXR-betaKi (nM)3.8N/AN/ADetails
TretinoinRetinoic acid receptor RXR-betaKi (nM)54N/AN/ADetails
TretinoinRetinoic acid receptor RXR-gammaKi (nM)11N/AN/ADetails
TretinoinRetinoic acid receptor RXR-gammaKi (nM)120N/AN/ADetails