A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

Abstract

Malaria is one of the most significant causes of childhood mortality but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective towards DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200–400 mg. DSM265 was well tolerated in repeat dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood and liver-stage activity, and predicted long human half-life position DSM265 as a new potential drug combination partner for either single-dose treatment or once weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive on the parasite liver-stage

Assessing drug efficacy against Plasmodium falciparum liver stages in vivo

“…DSM265 is a new antimalarial molecule that selectively targets Plasmodial DHODH and exhibits potent blood stage activity against P. falciparum both in vitro and in vivo, as well as good liver stage activity in vitro (16). Therefore, we were interested in assessing the activity of DSM265 in the FRG huHep model and in understanding its effect on P. falciparum liver stage development in vivo.…”

Current therapies and future possibilities for drug development against liver-stage malaria

“…However, this approach requires the knowledge of a validated or well-characterized molecular target. For example, the recent efforts to develop the first Plasmodium DHODH inhibitor led to the rational design and clinical development of a novel compound with liver-and blood-stage activity, DSM265 (55,56).…”

Antimalaria Drug Development & Pipeline

“…DSM265 (Phase I) inhibits Pf DHODH (Dihydroo rotate dehydrogenase (DHODH) is the enzyme which catalyzes the rate-limiting step of the de novo pyrimidine biosynthetic pathway) selectively over its human counterpart. It demonstrated good oral bioavailability in rats and was efficacious in vitro and in mouse [17]. Benzimidazole inhibiting PfDHODH (IC50 = 40nM) and parasite growth, has a decent bioavailability in rat (49%) [18].…”