A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

Margaret A. Phillips, Karen L. White, Sreekanth Kokkonda, Xiaoyi Deng, John White, Farah El Mazouni, Kennan Marsh, Diana R. Tomchick, Krishne Manjalanagara, Kakali Rani Rudra, Grennady Wirjanata, Rintis Noviyanti, Ric N. Price, Jutta Marfurt, David M. Shackleford, Francis C K Chiu, Michael Campbell, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Iñigo Angulo-BarturenMaria Santos Martinez, Maria Lafuente-Monasterio, Werner Kaminsky, Kigbafori Silue, Anne Marie Zeeman, Clemens Kocken, Didier Leroy, Benjamin Blasco, Emilie Rossignol, Thomas Rueckle, Dave Matthews, Jeremy N. Burrows, David Waterson, Michael J. Palmer, Pradipsinh K. Rathod, Susan A. Charman

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.

Original languageEnglish (US)
Pages (from-to)945-957
Number of pages13
JournalACS Infectious Diseases
Volume2
Issue number12
DOIs
StatePublished - Dec 9 2016

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Keywords

  • dihydroorotate dehydrogenase
  • malaria
  • Plasmodium
  • pyrimidine biosynthesis

ASJC Scopus subject areas

  • Infectious Diseases

Cite this

Phillips, M. A., White, K. L., Kokkonda, S., Deng, X., White, J., El Mazouni, F., Marsh, K., Tomchick, D. R., Manjalanagara, K., Rudra, K. R., Wirjanata, G., Noviyanti, R., Price, R. N., Marfurt, J., Shackleford, D. M., Chiu, F. C. K., Campbell, M., Jimenez-Diaz, M. B., Bazaga, S. F., ... Charman, S. A. (2016). A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria. ACS Infectious Diseases, 2(12), 945-957. https://doi.org/10.1021/acsinfecdis.6b00144