A clinical candidate targeting dihydroorotate dehydrogenase for the treatment of malaria with blood and liver stage activity

Abstract

Malaria is a deadly tropical disease that kills up to 0.6 million people yearly, mostly young children in Africa. Current drug therapies are threatened by drug resistance and the development of novel compounds that are active against drug resistant strains is essential to malarial control and eradication programs. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme for the biosynthesis of pyrimidines required for DNA and RNA synthesis in the parasite. We used a combination of high throughput screening and structure guided medicinal chemistry to optimize a triazolopyrimidine‐based series of DHODH inhibitors resulting in the selection of a clinical candidate for the treatment of malaria. We have shown that DHODH inhibitors have both blood and liver stage anti‐malarial activity, that they have potent activity in both in vitro and in vivo models of malaria and that they are active against a range of clinically drug resistant parasites. A compound called DSM265 was selected from the triazolopyrimidine series for clinical development. DSM265 was shown to have excellent safety during preclinical development. DSM265 has been shown to be a long acting compound with a pharmacokinetic profile that is expected to support single dose treatment or once weekly chemoprevention.Support or Funding InformationThis work was supported by funds from the United States National Institutes of Health grants, U01AI075594 (to MAP, PKR and SAC) and R01AI103947 (to MAP and PKR) and from Medicines for Malaria Venture (MMV).