title: Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate.
abstract: The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.
authors.affiliation: Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
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authors.affiliation: Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
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authors.affiliation: Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
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authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.
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authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York 10032, USA.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
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authors.affiliation: Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
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authors.lastname: Narayanan
authors.affiliation: AstraZeneca, Alderley Park, Cheshire SK10 4TF, UK.
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authors.affiliation: Department of Innovative Medicines, AstraZeneca India Pvt. Ltd., Bellary Road, Hebbal, Bangalore 560024, India.
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mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D006168:Guinea Pigs; D006207:Half-Life; D010963:Plasmodium falciparum / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats
chemical_list: D000588:Amines; D000962:Antimalarials; D011743:Pyrimidines
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