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Publication Abstract from PubMed

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.

Structure-guided lead optimization of triazolopyrimidine-ring substituents identifies potent Plasmodium falciparum dihydroorotate dehydrogenase inhibitors with clinical candidate potential.,Coteron JM, Marco M, Esquivias J, Deng X, White KL, White J, Koltun M, El Mazouni F, Kokkonda S, Katneni K, Bhamidipati R, Shackleford D, Barturen I, Ferrer S, Jimenez-Diaz MB, Gamo FJ, Goldsmith EJ, Charman B, Bathurst I, Floyd D, Matthews D, Burrows JN, Rathod PK, Charman SA, Phillips MA J Med Chem. 2011 Jun 22. PMID:21696174^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.