Nonsteroidal selective glucocorticoid modulators: The effect of C-5 alkyl substitution on the transcriptional activation/repression profile of 2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines
Nonsteroidal selective glucocorticoid modulators: The effect of C-5 alkyl substitution on the transcriptional activation/repression profile of 2,5-dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines
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DOI：
10.1021/jm010367u
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发表时间：
2001-12-06
影响因子：
7.3
通讯作者：
Lane, BC
中科院分区：
文献类型：
--
作者：
Elmore, SW;Coghlan, MJ;Lane, BC
本文介绍了一系列选择性糖皮质激素受体调节剂的制备和表征。四环喹啉核心上的非芳香族C-5取代的初步构效关系显示出对小的亲脂性侧链的偏好。在这个位置上的适当取代保持了促炎转录因子的转录抑制，同时减少了配体/糖皮质激素受体复合物的转录激活活性。本研究中描述的最佳化合物为烯丙基类似物18和环戊基类似物32。与泼尼松龙相比，这些候选物在报告基因测定中显示出略低的效力，高度有效的E-选择素抑制，糖皮质激素反应元件活化水平显著降低。在体内评价烯丙基类似物18。在葡聚糖凝胶诱导的肺嗜酸性粒细胞增多症模型中，18的口服剂量显示ED 50 = 1.7 mg/kg，而泼尼松龙为1.2 mg/kg，在角叉菜胶诱导的爪水肿模型中，泼尼松龙的ED 50 = 15 mg/kg，而泼尼松龙为4 mg/kg。
The preparation and characterization of a series of selective glucocorticoid receptor modulators are described. The preliminary structure-activity relationship of nonaromatic C-5 substitution on the tetracyclic quinoline core showed a preference for small lipophilic side chains. Proper substitution at this position maintained the transcriptional repression of proinflammatory transcription factors while diminishing the transcriptional activation activity of the ligand/glucocorticoid receptor complex. The optimal compounds described in this study were the allyl analogue 18 and cyclopentyl analogue 32. These candidates showed slightly less potent, highly efficacious E-selectin repression with significantly reduced levels of glucocorticoid response element activation in reporter gene assays vs prednisolone. Allyl analogue 18 was evaluated in vivo. An oral dose of 18 showed an ED50 = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED50 = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.