Novel Imidazol-1-ylmethyl Substituted 1,2,5,6-Tetrahydropyrrolo[3,2,1-ij]quinolin-4-ones as Potent and Selective CYP11B1 Inhibitors for the Treatment of Cushing's Syndrome

被引：64
作者：
Yin, Lina [1 ,2 ,3 ]
Lucas, Simon [1 ,2 ]
Maurer, Frauke [4 ]
Kazmaier, Uli [4 ]
Hu, Qingzhong [1 ,2 ]
Hartmann, Rolf W. [1 ,2 ]
机构：
[1] Univ Saarland, D-66123 Saarbrucken, Germany
[2] Helmholtz Inst Pharmaceut Res Saarland HIPS, D-66123 Saarbrucken, Germany
[3] Elexopharm GmbH, D-66123 Saarbrucken, Germany
[4] Univ Saarland, Inst Organ Chem, D-66123 Saarbrucken, Germany
来源：
JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 14期
关键词：
HUMAN 17-ALPHA-HYDROXYLASE-17,20-LYASE CYP17; ALDOSTERONE SYNTHASE INHIBITORS; BIOLOGICAL EVALUATION; DERIVATIVES; DISEASES; THERAPY; BIARYLS; ENZYME; SERIES;
D O I：
10.1021/jm3003872
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
CYP11B1 inhibition is a promising therapy for Cushing's syndrome. Starting from etomidate, references I and II, the title compounds were designed and synthesized. Cyclopropyl analogue 4 was identified as a CYP11B1 inhibitor more potent (IC50 = 2.2 nM) than leads and more selective (SF = 11) than I and metyrapone. Since it also showed potent inhibition of rat CYP11B1 and good selectivity over human CYP17 and CYP19, it is a promising candidate for further development.
引用
收藏
页码：6629 / 6633
页数：5
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