Novel drugs to treat human African trypanosomiasis (HAT) are still urgently needed despite the recent addition of nifurtimox-eflornithine combination therapy (NECT) to WHO Model Lists of Essential Medicines against second stage HAT, where parasites have invaded the central nervous system (CNS). The pharmacology of a potential orally available lead compound, N-methoxy-6-{5-[4-(N-methoxyamidino) phenyl]-furan-2-yl}-nicotinamidine (DB844), was evaluated in a vervet monkey model of second stage HAT, following promising results in mice. DB844 was administered orally to vervet monkeys, beginning 28 days post infection (DPI) with Trypanosoma brucei rhodesiense KETRI 2537. DB844 was absorbed and converted to the active metabolite 6-[5-(4-phenylamidinophenyl)-furanyl-2-yl]-nicotinamide (DB820), exhibiting plasma Cmax values of 430 and 190 nM for DB844 and DB820, respectively, after the 14th dose at 6 mg/kg qd. A 100-fold reduction in blood trypanosome counts was observed within 24 h of the third dose and, at the end of treatment evaluation performed four days post the last drug dose, trypanosomes were not detected in the blood or cerebrospinal fluid of any monkey. However, some animals relapsed during the 300 days of post treatment monitoring, resulting in a cure rate of 3/8 (37.5%) and 3/7 (42.9%) for the 5 mg/kg×10 days and the 6 mg/kg×14 days dose regimens respectively. These DB844 efficacy data were an improvement compared with pentamidine and pafuramidine both of which were previously shown to be non-curative in this model of CNS stage HAT. These data show that synthesis of novel diamidines with improved activity against CNS-stage HAT was possible. New drugs are needed to treat sleeping sickness, especially the second stage of the disease, which is characterised by the presence of parasites (trypanosomes) in the brain. The purpose of this work was to determine whether DB844, a new drug that is converted to the active form (DB820) after oral administration, has the potential to treat second stage sleeping sickness. Two dosing regimens of DB844 were evaluated in two groups of vervet monkeys that were infected experimentally with trypanosomes. Treatment was initiated four weeks after infection, when the monkeys were in second stage sleeping sickness, as confirmed by the presence of trypanosomes in brain fluid. Orally administered DB844 was well absorbed, tolerated and resulted in a decrease of trypanosomes in both the blood and brain fluid. However, some monkeys relapsed after treatment, with an overall cure rate of approximately 40% in both study groups. For at least two days after last dosing, the active drug, DB820, achieved blood concentrations known to be at least 19 times more than the minimum concentration that has been shown to be effective against a stringent human infective trypanosome isolate (STIB 900). These results represent an advance in efforts to develop new related compounds as oral treatments for sleeping sickness.