Druzgala P, Hochhaus G, Bodor N
Center for Drug Discovery, University of Florida, Gainesville.
J Steroid Biochem Mol Biol. 1991 Feb;38(2):149-54. doi: 10.1016/0960-0760(91)90120-t.
An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic acid (10(-5) M) in order to block transcortin binding sites. Loteprednol etabonate exhibited a binding affinity which was 4.3 times that of dexamethasone, both compounds having a Hill factor close to 1 whereas PJ90 and PJ91 did not show any affinity to the receptor. Loteprednol etabonate was compared to betamethasone 17 alpha-valerate in a vasoconstriction test which was performed on the forearm skin of human volunteers. The results showed that loteprednol etabonate has good skin-permeation properties and strong glucocorticoid activity.
实现了氯替泼诺乙酯（17α-乙氧基羰基氧基-11β-羟基-3-氧代雄甾-1,4-二烯-17β-羧酸氯甲酯）的改进合成。新型糖皮质激素的设计基于软药概念。在与[3H]曲安奈德的竞争性结合实验中，测定了氯替泼诺及其假定代谢物（PJ90和PJ91）与大鼠肺II型糖皮质激素受体的相对结合亲和力。培养基中含有皮质酸（10^(-5) M）以阻断皮质素结合位点。氯替泼诺乙酯的结合亲和力是地塞米松的4.3倍，两种化合物的希尔系数均接近1，而PJ90和PJ91对受体无任何亲和力。在人体志愿者的前臂皮肤上进行的血管收缩试验中，将氯替泼诺乙酯与倍他米松17α-戊酸酯进行了比较。结果表明，氯替泼诺乙酯具有良好的皮肤渗透性能和强大的糖皮质激素活性。
