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

Christel Brunschwig, Nina Lawrence, Dale Taylor, Efrem Abay, Mathew Njoroge, Gregory S. Basarab, Claire Le Manach, Tanya Paquet, Diego Gonzàlez Cabrera, Aloysius T. Nchinda, Carmen De Kock, Lubbe Wiesner, Paolo Denti, David Waterson, Benjamin Blasco, Didier Leroy, Michael J. Witty, Cristina Donini, James Duffy, Sergio WittlinKaren L. White, Susan A. Charman, Maria Belén Jiménez-Díaz, Iñigo Angulo-Barturen, Esperanza Herreros, Francisco Javier Gamo, Rosemary Rochford, Dalu Mancama, Theresa L. Coetzer, Mariëtte E. Van der Watt, Janette Reader, Lyn Marie Birkholtz, Kennan C. Marsh, Suresh M. Solapure, John E. Burke, Jacob A. McPhail, Manu Vanaerschot, David A. Fidock, Paul V. Fish, Peter Siegl, Dennis A. Smith, Grennady Wirjanata, Rintis Noviyanti, Ric N. Price, Jutta Marfurt, Kigbafori D. Silue, Leslie J. Street, Kelly Chibaleb

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

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.

Original languageEnglish
Article numbere00012-18
Number of pages16
JournalAntimicrobial Agents and Chemotherapy
Volume62
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • 1-phosphatidylinositol 4-kinase inhibitor
  • Absorption
  • Distribution metabolism
  • Drug discovery
  • Excretion
  • Human dose prediction
  • In vivo efficacy
  • Malaria
  • Pharmacokinetic/pharmacodynamic modeling
  • Pharmacokinetics
  • Plasmodium spp

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