2. Academic Validation
  3. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

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

  • ACS Infect Dis. 2016 Dec 9;2(12):945-957. doi: 10.1021/acsinfecdis.6b00144.
Margaret A Phillips,  Karen L White 1,  Sreekanth Kokkonda 2,  Xiaoyi Deng,  John White 2,  Farah El Mazouni,  Kennan Marsh 3,  Diana R Tomchick,  Krishne Manjalanagara 4,  Kakali Rani Rudra 4,  Grennady Wirjanata 5,  Rintis Noviyanti 6,  Ric N Price 5 7,  Jutta Marfurt 5,  David M Shackleford 1,  Francis C K Chiu 1,  Michael Campbell 1,  Maria Belen Jimenez-Diaz 8,  Santiago Ferrer Bazaga 8,  Iñigo Angulo-Barturen 8,  Maria Santos Martinez 8,  Maria Lafuente-Monasterio 8,  Werner Kaminsky 2,  Kigbafori Silue 9,  Anne-Marie Zeeman 10,  Clemens Kocken 10,  Didier Leroy 11,  Benjamin Blasco 11,  Emilie Rossignol 11,  Thomas Rueckle 11,  Dave Matthews 11,  Jeremy N Burrows 11,  David Waterson 11,  Michael J Palmer 11,  Pradipsinh K Rathod 2,  Susan A Charman 1
Affiliations

Affiliations

  • 1 Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
  • 2 Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
  • 3 AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064-6104, United States.
  • 4 Syngene International Ltd. , 560 099 Bangalore, India.
  • 5 Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University , P.O. Box 41096, Casuarina, NT 0811, Australia.
  • 6 Eijkman Institute for Molecular Biology , Jl. Diponegoro 69, 10430 Jakarta, Indonesia.
  • 7 Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford , Oxford OX3 7LJ, U.K.
  • 8 GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
  • 9 Centre Suisse de Recherches Scientifiques en Côte d'Ivoire , Km17, Route de Dabou, Adiopodoumé, BP 1303 Abidjan, Ivory Coast.
  • 10 Biomedical Primate Research Centre , 2288 GJ Rijswijk, The Netherlands.
  • 11 Medicines for Malaria Venture , 1215 Geneva, Switzerland.
PMID: 27641613 DOI: 10.1021/acsinfecdis.6b00144
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.

Keywords

Plasmodium; dihydroorotate dehydrogenase; malaria; pyrimidine biosynthesis.

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