Pharmacology of DB844, an Orally Active aza Analogue of Pafuramidine, in a Monkey Model of Second Stage Human African Trypanosomiasis

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 C max 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.

In Vitro , Ex Vivo , and In Vivo Activities of Diamidines against Trypanosoma congolense and Trypanosoma vivax

“…The activities and efficacies of diamidine (dicationic) compounds against a panel of different kinetoplastid parasites have previously been investigated (8)(9)(10), and these compounds have been demonstrated to have good efficacy against a variety of pathogens (11). Diamidines were also investigated for their in vitro activities and efficacies against T. evansi in animal models (12)(13)(14).…”

Bis-Benzimidazole Hits against Naegleria fowleri Discovered with New High-Throughput Screens

“…Several of these pyridyl diamidine derivatives achieve steady-state levels of 10 to 40 M in brain of rodents dosed orally, and in recent studies DB820 cured Vervet monkeys of late-stage HAT disease (15,33). DB844, a prodrug that is rapidly converted to DB820, dosed at 5 mg/kg of body weight once a day for 5 days, cured monkeys infected with T. brucei rodiesense in the late-stage disease model (34). In yet another model of CNS disease, two arylimidamides were active in BALB/c mice infected with the apicomplexan parasite Neospora caninum and significantly reduced the cerebral parasite burden (35).…”

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis

“…Several diamidine prodrugs have been tested in the GVR35 CNS mouse model, in which DB844 and DB868 administered orally cured CNS infections in mice (10). DB844 and DB868 have been further tested in the vervet monkey model of second-stage HAT, and results have been reported recently (15,16). DB868 was significantly better tolerated in vervet monkeys than was DB844 and could be a promising oral drug candidate, especially for first-stage disease (17).…”