DSM705 is a pyrrole-based inhibitor of Dihydroorotate Dehydrogenase (DHODH). It demonstrates high potency in the nanomolar range against Plasmodium DHODH and Plasmodium parasites, while not interfering with mammalian DHODHs. DSM705 shows significant efficacy as an antimalarial compound.

DHODH (P. vivax):52 nM (IC50), DHODH (P. falciparum):95 nM (IC50)

DSM705 exhibits inhibitory activity against both P. falciparum DHODH (Pf DHODH, IC50=95 nM) and P. vivax DHODH (Pv DHODH, IC50=52 nM), as well as Pf 3D7 cells (EC50=12 nM), without inhibiting the human counterpart of the enzyme[1].

DSM705, when administered orally at doses ranging from 3-200 mg/kg twice daily for 6 days, achieves optimal parasite eradication at a 50 mg/kg dosage, completely eliminating parasitemia by the 7th or 8th day. In Swiss outbred mice, a single oral dose of DSM705 at 2.6 and 24 mg/kg demonstrates high oral bioavailability (74%, 70%), extended half-life (3.4, 4.5 hours), and peak concentration (C max) values of 2.6 and 20 μM, respectively. Furthermore, a single intravenous dose of 2.3 mg/kg in mice results in a clearance rate (CL) of 2.8 mL/min/kg and a steady-state volume of distribution (V ss) of 1.3 L/kg. The efficacy of DSM705 was tested in SCID mice inoculated with parasites, with oral doses (p.o.) administered twice daily for 6 days across varying concentrations (3, 10, 20, 50, 100, 200 mg/kg), demonstrating dose-dependent parasite eradication and complete suppression of parasitemia by days 7-8. Similarly, pharmacokinetic analysis in Swiss Outbred Mice with doses of 2.6 and 24 mg/kg for oral administration and 2.3 mg/kg for intravenous (i.v.) administration showed notable outcomes in bioavailability, half-life, concentration maxima, clearance, and distribution volume.