7 H-Pyrrolo[2,3- d]pyrimidin-4-amine-Based Inhibitors of Calcium-Dependent Protein Kinase 1 Have Distinct Inhibitory and Oral Pharmacokinetic Characteristics Compared with 1 H-Pyrazolo[3,4- d]pyrimidin-4-amine-Based Inhibitors.
7 H-Pyrrolo[2,3- d]pyrimidin-4-amine-Based Inhibitors of Calcium-Dependent Protein Kinase 1 Have Distinct Inhibitory and Oral Pharmacokinetic Characteristics Compared with 1 H-Pyrazolo[3,4- d]pyrimidin-4-amine-Based Inhibitors.
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DOI：
10.1021/acsinfecdis.7b00224
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发表时间：
2018-04-13
影响因子：
5.3
通讯作者：
Maly DJ
中科院分区：
文献类型：
--
作者：
Vidadala RSR;Golkowski M;Hulverson MA;Choi R;McCloskey MC;Whitman GR;Huang W;Arnold SLM;Barrett LK;Fan E;Merritt EA;Van Voorhis WC;Ojo KK;Maly DJ
基于 1H-吡唑并[3,4-d]嘧啶-4-胺（吡唑并嘧啶，PP）支架的隐孢子虫钙依赖性蛋白激酶 1 (CpCDPK1) 选择性抑制剂在隐孢子虫病的体外和体内模型中均有效。然而，对独特的安全性和药代动力学（PK）特性的探索促使我们探索替代支架。在这里，我们描述了一系列基于 7H-吡咯并[2,3-d]嘧啶-4-胺（吡咯并嘧啶，PrP）的 PP CpCDPK1 抑制剂类似物。大多数基于 PrP 的抑制剂可有效抑制 CpCDPK1 酶，对哺乳动物细胞无毒性，并可在低微摩尔范围内阻止微小隐孢子虫寄生虫的增殖。有趣的是，当从 PP 支架上展示时，某些取代基显示出 CpCDPK1 效力降低，但在 PrP 支架上却显着增强了功效。对这些配对化合物的 PK 研究表明，一些 PrP 类似物与其 PP 类似物相比具有不同的理化性质。这些结果表明，基于 PrP 支架的抑制剂是先前开发的 PP 抑制剂的独特治疗替代品。
Selective inhibitors of Cryptosporidium Calcium-Dependent Protein Kinase 1 (CpCDPK1) based on the 1H-pyrazolo[3,4-d]pyrimidin-4-amine (pyrazolopyrimidine, PP) scaffold are effective in both in vitro and in vivo models of cryptosporidiosis. However, the search for distinct safety and pharmacokinetic (PK) properties has motivated our exploration of alternative scaffolds. Here, we describe a series of 7H-pyrrolo[2,3-d]pyrimidin-4-amine (pyrrolopyrimidine, PrP)-based analogs of PP CpCDPK1 inhibitors. Most of the PrP-based inhibitors described potently inhibit the CpCDPK1 enzyme, demonstrate no toxicity against mammalian cells, and block proliferation of the C. parvum parasite in the low micromolar range. Interestingly, certain substituents that show reduced CpCDPK1 potency when displayed from a PP scaffold provided notably enhanced efficacy in the context of a PrP scaffold. PK studies on these paired compounds show that some PrP analogs have distinct physiochemical properties compared with their PP counterparts. These results demonstrate that inhibitors based on a PrP scaffold are distinct therapeutic alternatives to previously developed PP inhibitors.
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影响因子：
168.9
作者：
Kotloff, Karen L.;Nataro, James P.;Levine, Myron M.
通讯作者：
Levine, Myron M.
影响因子：
2.7
作者：
Huang, Wenlin;Hulverson, Matthew A.;Ojo, Kayode K.
通讯作者：
Ojo, Kayode K.
影响因子：
6.4
作者：
Schaefer, Deborah A.;Betzer, Dana P.;Riggs, Michael W.
通讯作者：
Riggs, Michael W.
影响因子：
2.4
作者：
Keyloun KR;Reid MC;Choi R;Song Y;Fox AMW;Hillesland HK;Zhang Z;Vidadala R;Merritt EA;Lau AOT;Maly DJ;Fan E;Barrett LK;Van Voorhis WC;Ojo KK
通讯作者：
Ojo KK
影响因子：
4.9
作者：
Huang, Wenlin;Choi, Ryan;Fan, Erkang
通讯作者：
Fan, Erkang