pd-156252 and Malaria

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

Topics: Administration, Oral; Animals; Antimalarials; Dihydroorotate Dehydrogenase; Humans; In Vitro Techniques; Malaria; Male; Mice; Microsomes, Liver; Models, Molecular; Oxidoreductases Acting on CH-CH Group Donors; Parasitic Sensitivity Tests; Plasmodium berghei; Plasmodium falciparum; Pyrimidines; Structure-Activity Relationship; Thiazoles; Triazoles