Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents

被引：49

作者：

Choi, Jun Yong ^{[1
]}

Calvet, Claudia M. ^{[3
,4
]}

Gunatilleke, Shamila S. ^{[3
,4
]}

Ruiz, Claudia ^{[2
]}

Cameron, Michael D. ^{[2
]}

McKerrow, James H. ^{[3
,4
]}

Podust, Larissa M. ^{[3
,4
]}

Roush, William R. ^{[1
]}

机构：

[1] Scripps Florida, Dept Chem, Jupiter, FL 33458 USA

[2] Scripps Florida, Dept Mol Therapeut, Jupiter, FL 33458 USA

[3] Univ Calif San Francisco, Ctr Discovery & Innovat Parasit Dis, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 19期

关键词：

STEROL 14-DEMETHYLASE INHIBITORS; ANTIFUNGAL AGENTS; ANTITRYPANOSOMAL THERAPY; CANCER DRUG; DISEASE; RESISTANCE; CHEMISTRY; DISCOVERY; MODEL;

D O I：

10.1021/jm401067s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (K-D <= 42 nM; EC50 = 0.65 mu M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYR51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 mu M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.

引用

页码：7651 / 7668

页数：18

共 26 条

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