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

GlaxoSmithKline, Diseases of the Developing World (DDW)-Tres Cantos Medicines Development Campus, Madrid, Spain.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 06/2011; 54(15):5540-61. DOI: 10.1021/jm200592f
Source: 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 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.

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Available from: Jeremy N Burrows
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    • "To provide an insight into the structural basis for potency and species selective binding of malariaspecific inhibitors, the first X-ray crystal structures of PfDHOD bound to triazolopyrimidine inhibitors were reported (Coteron et al. 2011). The conformational flexibility of triazolopyrimidines resulted in Fig. 3. Potent inhibitors of human DHOD and active metabolite of Lefluomide A77-1726. "
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    • "As a positive control, we also tested two anti-parasite dihydrofolate reductase inhibitors, pyrimethamine (recently shown to induce apoptosis in melanoma cells [58]) and P-218 [59], which were anticipated to show some activity against a human cancer cell panel. In addition we tested the highly selective parasite dihydroorotate dehydrogenase (DHODH) inhibitor DSM265 [60], and MMV 390048, a highly active anti-plasmodial compound which is a putative kinase inhibitor. Due to their high selectivity for parasite cells, these compounds were expected to be largely inactive. "
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    • "It is now replaced by more recent analogues without cross resistance: amodiaquine, piperaquine and the ‘quinacrine-amodiaquine’ hybrid, pyronaridine. Structures of these molecules and other clinical derivatives of each class are shown in Fig. 1 (Burrows et al. 2011). "
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