Potent and Selective Inhibitors of CDPK1 from T. gondii and C. parvum Based on a 5-Aminopyrazole-4-carboxamide Scaffold

被引：49

作者：

Zhang, Zhongsheng ^{[1
]}

Ojo, Kayode K. ^{[2
]}

Vidadala, RamaSubbaRao ^{[3
]}

Huang, Wenlin ^{[1
]}

Geiger, Jennifer A. ^{[4
]}

Scheele, Suzanne ^{[4
]}

Choi, Ryan ^{[2
]}

Reid, Molly C. ^{[2
]}

Keyloun, Katelyn R. ^{[2
]}

Rivas, Kasey ^{[2
]}

Siddaramaiah, Latha Kallur ^{[1
]}

Comess, Kenneth M. ^{[5
]}

Robinson, Kenneth P. ^{[5
]}

Merta, Philip J. ^{[5
]}

Kifle, Lemma ^{[5
]}

Hol, Wim G. J. ^{[1
]}

Parsons, Marilyn ^{[4
]}

Merritt, Ethan A. ^{[1
]}

Maly, Dustin J. ^{[3
]}

Verlinde, Christophe L. M. J. ^{[1
]}

Van Voorhis, Wesley C. ^{[2
]}

Fan, Erkang ^{[1
]}

机构：

[1] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[2] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA

[3] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[4] Seattle Biomed Res Inst, Seattle, WA 98109 USA

[5] AbbVie, Global Pharmaceut R&D, High Throughput Biol, N Chicago, IL 60064 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Toxoplasma gondii; Cryptosporidium parvum; calcium-dependent protein kinase-1; enzyme inhibitor; selectivity; PROTEIN-KINASE; 1; MAP KINASE; BINDING; CHILDREN;

D O I：

10.1021/ml400315s

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known "bumped kinase inhibitor" to create selective inhibitors of calcium-dependent protein kinase-1 from both Toxoplasma gondii and Cryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities in T. gondii cell proliferation assays and were shown to be nontoxic to mammalian cells.

引用

页码：40 / 44

页数：5

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