Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential

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• 作者：Jose M. Coteron ; Mari虂a Marco ; Jorge Esquivias ; Xiaoyi Deng ; Karen L. White ; John White ; Maria Koltun ; Farah El Mazouni ; Sreekanth Kokkonda ; Kasiram Katneni ; Ravi Bhamidipati ; David M. Shackleford ; In虄igo Angulo-Barturen ; Santiago B. Ferrer ; Mari虂a Bele虂n Jime虂nez-Di虂az ; Francisco-Javier Gamo ; Elizabeth J. Goldsmith ; William N. Charman ; Ian Bathurst ; David Floyd ; David Matthews ; Jeremy N. Burrows ; Pradipsinh K. Rathod ; Susan A. Charman ; Margaret A. Phillips
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 11, 2011
• 年：2011
• 卷：54
• 期：15
• 页码：5540-5561
• 全文大小：1285K
• 年卷期：v.54,no.15(August 11, 2011)
• ISSN：1520-4804

文摘

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 antimalarials, 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 toward clinical candidate status.