Tetrafluorophenoxymethyl ketone cruzain inhibitors with improved pharmacokinetic properties as therapeutic leads for Chagas' disease

被引：23

作者：

Neitz, R. Jeffrey ^{[1
,2
]}

Bryant, Clifford ^{[1
,2
]}

Chen, Steven ^{[1
,2
]}

Gut, Jiri ^{[1
,2
]}

Caselli, Estefania Hugo ^{[1
,2
]}

Ponce, Servando ^{[1
,2
]}

Chowdhury, Somenath ^{[3
]}

Xu, Haichao ^{[3
]}

Arkin, Michelle R. ^{[1
,2
]}

Ellman, Jonathan A. ^{[3
]}

Renslo, Adam R. ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Small Mol Discovery Ctr, San Francisco, CA 94158 USA

[2] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[3] Yale Univ, Dept Chem, New Haven, CT 06520 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 21期

关键词：

Chagas' disease; Cruzain; Protease inhibitors; Pharmacokinetics; Lead optimization; LYSOSOMOTROPISM; TARGET;

D O I：

10.1016/j.bmcl.2015.06.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of the cysteine protease cruzain from Trypanosoma cruzi has been studied pre-clinically as a new chemotherapeutic approach to treat Chagas' disease. Efficacious effects of vinylsulfone-based cruzain inhibitors in animal models support this therapeutic hypothesis. More recently, substrate-activity screening was used to identify nonpeptidic tetrafluorophenoxymethyl ketone inhibitors of cruzain that showed promising efficacy in animal models. Herein we report efforts to further optimize the in vitro potency and in vivo pharmacokinetic properties of this new class of cruzain inhibitors. Through modifications of the P1, P2 and/or P3 positions, new analogs have been identified with reduced lipophilicity, enhanced potency, and improved oral exposure and bioavailability. (C) 2015 Elsevier Ltd. All rights reserved.

引用

收藏

页码：4834 / 4837

页数：4

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