Open AccessA Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria
Author(s) -
Margaret A. Phillips,
Karen L. White,
Sreekanth Kokkonda,
Xingming Deng,
John White,
Farah El Mazouni,
Kennan C. Marsh,
Diana R. Tomchick,
Krishne Manjalanagara,
Kakali Rani Rudra,
Grennady Wirjanata,
Rintis Noviyanti,
Ric N. Price,
Jutta Marfurt,
David M. Shackleford,
Francis Chi Keung Chiu,
Michael G. Campbell,
Marı́a Belén Jiménez-Dı́az,
Santiago Ferrer-Bazaga,
Iñigo Angulo-Barturén,
María Santos Martínez,
María José Lafuente-Monasterio,
Werner Kaminsky,
Kigbafori D. Silué,
AnneMarie Zeeman,
Clemens H. M. Kocken,
Didier Leroy,
Benjamin Blasco,
Emilie Rossignol,
Thomas Rueckle,
M. A. Dave,
Jeremy N. Burrows,
David Waterson,
Michael J. Palmer,
Pradipsinh K. Rathod,
Susan A. Charman
Publication year - 2016
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.6b00144
Subject(s) - dihydroorotate dehydrogenase , malaria , pharmacology , plasmodium falciparum , primaquine , plasmodium vivax , drug , drug development , biology , medicine , immunology , biochemistry , enzyme , chloroquine
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 SF 5 -aniline moiety of DSM265 with a series of CF 3 -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.