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 shows inhibitory activity against P. falciparum DHODH ( Pf DHODH, IC 50 =95 nM), P. vivax DHODH ( Pv DHODH, IC 50 =52 nM) and Pf 3D7 cells (EC 50 =12 nM), with no inhibition of the human enzyme[1].

DSM705 (3-200 mg/kg; p.o. twice a day for 6 days) provides the maximum rate of parasite killing at the dose of 50 mg/kg and fully suppresses parasitemia by days 7-8[1]. DSM705 (2.6 and 24 mg/kg; a single p.o.) exhibits high oral bioavailability (74%, 70%), apparent t 1/2 (3.4, 4.5 h) and C max (2.6, 20 μM) in Swiss outbred mice[1]. DSM705 (2.3 mg/kg; a single i.v.) exhibits plasma clearance (CL=2.8 mL/min/kg) and V ss (1.3 L/kg) in mice[1]. Animal Model: SCID mice were inoculated with parasites[1]Dosage: 3, 10, 20, 50, 100, 200 mg/kg Administration: P.o. twice a day for 6 days Result: Killed parasite in a dose dependent manner and fully suppressed parasitemia by days 7-8. Animal Model: Swiss Outbred Mice[1]Dosage: 2.6 and 24 mg/kg for p.o.; 2.3 mg/kg for i.v. (Pharmacokinetic Analysis) Administration: A single p.o. and i.v. Result: P.o.: F=74/70%, t 1/2 =3.4/4.5 h, C max =2.6/20 μM. I.v.: CL=2.8 mL/min/kg, V ss =1.3 L/kg.