1. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
- Author
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Krishne Manjalanagara, Margaret A. Phillips, Xiaoyi Deng, Michael Campbell, Karen L. White, Ric N. Price, Kennan C. Marsh, Jeremy N. Burrows, John H. White, Werner Kaminsky, Anne Marie Zeeman, Sreekanth Kokkonda, Susan A. Charman, Diana R. Tomchick, Santiago Ferrer Bazaga, Clemens H. M. Kocken, Grennady Wirjanata, Francis C. K. Chiu, María Santos Martínez, David M. Shackleford, María Belén Jiménez-Díaz, Kigbafori D. Silué, Thomas Rueckle, Jutta Marfurt, Kakali Rani Rudra, Benjamin Blasco, Iñigo Angulo-Barturen, Rintis Noviyanti, Pradipsinh K. Rathod, Maria J. Lafuente-Monasterio, Michael J. Palmer, Dave Matthews, Emilie Rossignol, David Waterson, Didier Leroy, and Farah El Mazouni
- Subjects
0301 basic medicine ,Drug ,Plasmodium ,Oxidoreductases Acting on CH-CH Group Donors ,dihydroorotate dehydrogenase ,media_common.quotation_subject ,Plasmodium falciparum ,030106 microbiology ,Dihydroorotate Dehydrogenase ,malaria ,Protozoan Proteins ,pyrimidine biosynthesis ,Biology ,Pharmacology ,Article ,Antimalarials ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,Dogs ,parasitic diseases ,medicine ,Animals ,Humans ,Structure–activity relationship ,Dosing ,Enzyme Inhibitors ,Malaria, Falciparum ,Dihydroorotate Dehydrogenase Inhibitor ,media_common ,chemistry.chemical_classification ,medicine.disease ,biology.organism_classification ,Rats ,Pyrimidines ,030104 developmental biology ,Infectious Diseases ,Enzyme ,chemistry ,Dihydroorotate dehydrogenase ,Malaria - 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 (
- Published
- 2016
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