Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB

被引：51

作者：

Mallari, Jeremy P. ^{[1
,3
]}

Shelat, Anang A. ^{[3
]}

Obrien, Terri ^{[2
]}

Caffrey, Conor R. ^{[2
]}

Kosinski, Aaron ^{[3
]}

Connelly, Michele ^{[3
]}

Harbut, Michael ^{[4
]}

Greenbaum, Doron ^{[4
]}

McKerrow, James H. ^{[2
]}

Guy, R. Kiplin ^{[1
,3
]}

机构：

[1] Univ Calif San Francisco, Grad Program Chem & Chem Biol, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA

[3] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[4] Univ Penn, Dept Pharmacol, Philadelphia, PA 19146 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 03期

关键词：

BLOOD-STREAM FORMS; CYSTEINE PROTEASES; CATHEPSINS B; IN-VITRO; BRUCEI; DEGRADATION; TRANSPORTER; RHODESAIN;

D O I：

10.1021/jm070760l

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T brucei in vitro (Mackey, Z. B.; O'Brien, T. C.; Greenbaum, D. C.; Blank, R. B.; McKerrow, J. H. J. Biol. Chem. 2004, 279, 48426-48433). Herein, we describe the first inhibitors of TbcatB, a series of purine nitriles. The compounds are potent trypanocides, killing the parasite with a high degree of selectivity over a panel of three human cell lines. In addition, a predictive model of trypanocidal activity was developed on the basis of potency against TbcatB and various calculated physical property descriptors.

引用

页码：545 / 552

页数：8

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