Abstract:
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/kg610 days and the 6 mg/kg614 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.
