Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11β-hydroxysteroid dehydrogenase type I

被引：12

作者：

Valeur, Eric ^{[1
]}

Christmann-Franck, Serge ^{[1
]}

Lepifre, Franck ^{[1
]}

Carniato, Denis ^{[1
]}

Cravo, Daniel ^{[1
]}

Charon, Christine ^{[1
]}

Bozec, Sophie ^{[1
]}

Musil, Djordje ^{[2
]}

Hillertz, Per ^{[2
]}

Doare, Liliane ^{[1
]}

Schmidlin, Fabien ^{[1
]}

Lecomte, Marc ^{[1
]}

Schultz, Melanie ^{[2
]}

Roche, Didier ^{[1
]}

机构：

[1] Merck Serono SA, CH-1202 Geneva, Switzerland

[2] Merck Serono, D-64293 Darmstadt, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 18期

关键词：

BETA-HYDROXYSTEROID DEHYDROGENASE; PROTEIN-LIGAND DOCKING; 11-BETA-HSD1; INHIBITORS; THERAPEUTIC TARGET; DRUG DISCOVERY; LOCALIZATION; OBESITY; RAT; HIPPOCAMPUS; BINDING;

D O I：

10.1016/j.bmcl.2012.07.070

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Indole-pyrrolidines were identified as inhibitors of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC50 potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11 beta-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11 beta-HSD1 (IC50 < 1 mu M) in a cellular model (3T3L1 adipocytes) (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5909 / 5914

页数：6

共 33 条

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