DSM421

DSM421 is an orally bioavailable triazolopyrimidine small-molecule inhibitor of Plasmodium dihydroorotate dehydrogenase (PfDHODH), developed as a backup to DSM265 for the treatment and chemoprevention of malaria caused by Plasmodium falciparum and Plasmodium vivax.[1][2][9] By selectively blocking parasite DHODH, a key mitochondrial enzyme in de novo pyrimidine biosynthesis, DSM421 depletes nucleotide pools and inhibits parasite replication, with equal potency against P. falciparum and P. vivax blood stages and prophylactic activity against liver stages in preclinical models.[1][2] Compared with DSM265, DSM421 exhibits improved solubility, lower intrinsic clearance, higher plasma exposure, and better selectivity versus mammalian and rodent DHODH, supporting once-daily oral dosing and a target product profile of single-dose cure or once-weekly chemoprevention; it advanced into early clinical development with Medicines for Malaria Venture and Takeda but was not progressed further due to off-target toxicity identified in preclinical safety studies.[1][2][4][5][9][10][11]