Brewster M E, Bartruff M S, Anderson W R, Druzgala P J, Bodor N, Pop E
Pharmos, Corporation, Alachua, Florida 32615.
J Med Chem. 1994 Nov 25;37(24):4237-44. doi: 10.1021/jm00050a020.
The structural parameters important for biological efficacy of an estradiol chemical delivery system (CDS), a brain-targeting approach based on redox trapping, were examined by molecular manipulation of a prototype derivative, estradiol 17-(1-methyl-1, 4-dihydronicotinate) (E2-CDS). Seven E2-CDS analogs in which the N-methyl substituent was altered were prepared including N-substituted short and medium straight chain alkyl, short branched chain alkyl, and aralkyl derivatives. Chemical and in vitro testing indicated that the most stable derivative was the N-benzyl E2-CDS. The analogs were tested in an intact male rat model to assess various central estrogenic manifestations including the rate of body weight gain, serum E2 and testosterone concentrations, and seminal vesicle, prostate and pituitary weight changes. Results indicated that all prepared CDS derivatives exerted some degree of central estrogenization with the most potent compounds being the parent E2-CDS and its ethyl homologue. Importantly, while the ethyl E2-CDS was equipotent to E2-CDS in various biological assays, it did not significantly elevate serum E2 compared to vehicle control at day 14.
通过对原型衍生物雌二醇17-(1-甲基-1,4-二氢烟酸酯)(E2-CDS)进行分子操作，研究了基于氧化还原捕获的脑靶向方法——雌二醇化学递送系统(CDS)生物活性的重要结构参数。制备了7种N-甲基取代基发生改变的E2-CDS类似物，包括N-取代的短链和中链直链烷基、短支链烷基和芳烷基衍生物。化学和体外测试表明，最稳定的衍生物是N-苄基E2-CDS。在完整雄性大鼠模型中对这些类似物进行测试，以评估各种中枢雌激素表现，包括体重增加率、血清E2和睾酮浓度以及精囊、前列腺和垂体重量变化。结果表明，所有制备的CDS衍生物都表现出一定程度的中枢雌激素化，其中最有效的化合物是母体E2-CDS及其乙基同系物。重要的是，虽然乙基E2-CDS在各种生物学试验中与E2-CDS等效，但在第14天时，与溶剂对照组相比，它并没有显著提高血清E2水平。
