Randolph John T, Waid Philip, Nichols Charles, Sauer Daryl, Haviv Fortuna, Diaz Gilbert, Bammert Gary, Besecke Leslie M, Segreti Jason A, Mohning Kurt M, Bush Eugene N, Wegner Craig D, Greer Jonathan
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
J Med Chem. 2004 Feb 26;47(5):1085-97. doi: 10.1021/jm030418i.
The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.
本文描述了一系列新型非肽类促黄体激素释放激素（LHRH）拮抗剂——6-O-甲基红霉素A的11,12-环氨基甲酸酯衍生物的设计与合成。在对我们的化学库进行筛选过程中发现的大环内酯类拮抗剂1，通过分子建模与大环肽拮抗剂2进行了比较，从而为设计更有效的拮抗剂提供了模型。在对红霉内酯核心结构3位上的克拉定糖寻找替代物的药物化学研究中，得到了一系列恶唑烷酮氨基甲酸酯，其活性与含克拉定糖的母体大环内酯类相当。去克拉定糖LHRH拮抗剂14对大鼠和人LHRH受体均具有1 - 2 nM的亲和力，并且在体外是促黄体生成素（LH）释放的强效抑制剂（pA2 = 8.76）。在体内，通过静脉注射和口服给药，发现14在雄性去势大鼠中可产生剂量依赖性的LH抑制作用。
