Uct943, a next-generation plasmodium falciparum pi4k inhibitor preclinical candidate for the treatment of malaria

Abstract

The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium 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 Plasmodium falciparum and Plasmodium vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in Plasmodium berghei and humanized P. falciparum NOD-scid IL-2Rnull mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vivo 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 Plasmodium 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. We acknowledge the following: Nesia Barnes and Warren Olifant from H3D, University of Cape Town (South Africa), for the ADME assays; Virgil Verhoog and Sumaya Salie from H3D, University of Cape Town (South Africa), for the P. falciparum blood stage assays; Trevor Finch from the Division of Pharmacology, University of Cape Town (South Africa), for assistance with the animal work; Michael Delves, Andrea Ruecker, and Robert E. Sinden from the Cell and Molecular Biology laboratory, Imperial College, London (United Kingdom), for the gamete formation assay; Anne-Marie Zeeman and Clemens H. M Kocken from the Biomedical Primate Research Centre, Rijswijk (The Netherlands), for the P. cynomolgi in vitro prophylactic and radical cure assay; and Rachaneeporn Jenwithisuk from the Faculty of Tropical Medicine, Mahidol University, Bangkok (Thailand), for the Pv in vitro prophylactic and radical cure assay. We acknowledge the Medicines for Malaria Venture (projects MMV09/0002 and 08/0015), Technology Innovation Agency (TIA), the NIH (R01 AI103058 to D.A.F.) and the Strategic Health Innovation Partnerships (SHIP) unit of the South African Medical Research Council (SAMRC) for financial support of this research. K.C. acknowledges support from the University of Cape Town, SAMRC, and South African Research Chairs Initiative of the Department of Science and Technology administered through the National Research Foundation. L.-M.B. and T.L.C. also acknowledge support of SHIP.