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<jats:title>ABSTRACT</jats:title><jats:p>The 2-aminopyridine MMV048 was the first drug candidate inhibiting<jats:named-content content-type="genus-species">Plasmodium</jats:named-content>phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite life cycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activities than MMV048 and was more potent against resistant<jats:named-content content-type="genus-species">Plasmodium falciparum</jats:named-content>and<jats:named-content content-type="genus-species">Plasmodium vivax</jats:named-content>clinical isolates. Excellent<jats:italic>in vitro</jats:italic>antiplasmodial activity translated into high efficacy in<jats:named-content content-type="genus-species">Plasmodium berghei</jats:named-content>and humanized<jats:named-content content-type="genus-species">P. falciparum</jats:named-content>NOD-<jats:italic>scid IL-2R</jats:italic>γ<jats:sup><jats:italic>null</jats:italic></jats:sup>mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate<jats:italic>in vivo</jats:italic>intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next-generation<jats:named-content content-type="genus-species">Plasmodium</jats:named-content>PI4K inhibitor, UCT943, based on the combined preclinical data, has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent, and block the transmission of malaria.</jats:p>

Original publication

DOI

10.1128/aac.00012-18

Type

Journal article

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

25/06/2018

Volume

62