Boehm M F, Zhang L, Zhi L, McClurg M R, Berger E, Wagoner M, Mais D E, Suto C M, Davies J A, Heyman R A
Department of Retinoid Chemistry Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
J Med Chem. 1995 Aug 4;38(16):3146-55. doi: 10.1021/jm00016a018.
Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.
维甲酸X受体（RXR）选择性化合物4-[1-(3,5,5,8,8-五甲基-5,6,7,8-四氢-2-萘基)乙烯基]苯甲酸（LGD1069）目前正处于针对癌症和皮肤病适应症的I/IIA期临床试验阶段，其结构修饰已导致鉴定出对RXR具有超过1000倍选择性的效力越来越强的维甲酸。本文描述了一系列RXR选择性维甲酸的设计与制备，以及从共转染和竞争性结合试验中获得的生物学数据，这些试验用于评估它们的效力和选择性。最具效力和选择性的类似物是6-[1-(3,5,5,8,8-五甲基-5,6,7,8-四氢萘-2-基)环丙基]烟酸（12d；LG100268）。该化合物已被证明可用于研究RXR依赖性生物学途径，包括程序性细胞死亡（PCD）的诱导和转谷氨酰胺酶（TGase）活性。我们的研究表明，人白血病髓细胞中PCD和TGase的诱导依赖于RXR介导途径的激活。
