Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.
Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.
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结构引导的三唑嘧啶环取代基的铅优化鉴定出具有临床候选潜力的有效的恶性疟原虫二氢二酸二氢二酸脱氢酶抑制剂。
DOI：
10.1021/jm200592f
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发表时间：
2011-08-11
影响因子：
7.3
通讯作者：
Phillips, Margaret A.
中科院分区：
文献类型：
--
作者：
Coteron, Jose M.;Marco, Maria;Esquivias, Jorge;Deng, Xiaoyi;White, Karen L.;White, John;Koltun, Maria;El Mazouni, Farah;Kokkonda, Sreekanth;Katneni, Kasiram;Bhamidipati, Ravi;Shackleford, David M.;Angulo-Barturen, Inigo;Ferrer, Santiago B.;Belen Jimenez-Diaz, Maria;Gamo, Francisco-Javier;Goldsmith, Elizabeth J.;Charman, William N.;Bathurst, Ian;Floyd, David;Matthews, David;Burrows, Jeremy N.;Rathod, Pradipsinh K.;Charman, Susan A.;Phillips, Margaret A.
药物治疗是抗疟治疗的主要手段，但目前的药物受到耐药性发展的威胁。为了鉴定新的潜在抗疟药，我们围绕先前鉴定的基于三唑并嘧啶的恶性疟原虫二氢乳清酸脱氢酶（PfDHODH）抑制剂系列进行了先导优化程序。PfDHODH的X射线结构用于通知药物化学程序，允许鉴定通过DHODH抑制作用杀死寄生虫的敏感和耐药菌株的有效和选择性抑制剂（DSM 265）。该化合物在人源化SCID小鼠恶性疟原虫模型中具有与氯喹相似的效力，可以通过简单的途径合成，并且啮齿动物药代动力学研究表明其具有优异的口服生物利用度、长半衰期和低清除率。这些研究已经确定了三唑并嘧啶系列中第一个符合先前确立的疗效和ADME性质进展标准的候选药物，证明了该化合物进一步开发为临床候选药物的合理性。
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by the development of resistance. In an effort to identify new potential anti-malarials we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure of PfDHODH was used to inform the medicinal chemistry program allowing the identification of a potent and selective inhibitor (DSM265) that acts through DHODH inhibition to kill both sensitive and drug resistant strains of the parasite. This compound has similar potency to chloroquine in the humanized SCID mouse P. falciparum model, can be synthesized by a simple route, and rodent pharmacokinetic studies demonstrated it has excellent oral bioavailability, a long half-life and low clearance. These studies have identified the first candidate in the triazolopyrimidine series to meet previously established progression criteria for efficacy and ADME properties, justifying further development of this compound towards clinical candidate status.
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影响因子：
1.5
作者：
Ganesan, Suresh M.;Morrisey, Joanne M.;Ke, Hangjun;Painter, Heather J.;Laroiya, Kamal;Phillips, Margaret A.;Rathod, Pradipsinh K.;Mather, Michael W.;Vaidya, Akhil B.
通讯作者：
Vaidya, Akhil B.
影响因子：
3.6
作者：
ALLEN, CFH;BEILFUSS, HR;VANALLAN, JA
通讯作者：
VANALLAN, JA
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
4.9
作者：
Belen Jimenez-Diaz, Maria;Mulet, Teresa;Angulo-Barturen, Inigo
通讯作者：
Angulo-Barturen, Inigo
影响因子：
7.3
作者：
Gujjar R;El Mazouni F;White KL;White J;Creason S;Shackleford DM;Deng X;Charman WN;Bathurst I;Burrows J;Floyd DM;Matthews D;Buckner FS;Charman SA;Phillips MA;Rathod PK
通讯作者：
Rathod PK