Discovery of Novel Orally Bioavailable Oxaborole 6-Carboxamides That Demonstrate Cure in a Murine Model of Late-Stage Central Nervous System African Trypanosomiasis

Abstract

(32), and treatment failures of up to 25% have been reported (12, 13). Difluoromethylornithine (DFMO) (Ornidyl) requires a 2-week therapy regimen which is difficult to administer in rural clinics (34). A new combination therapy with DFMO and oral nifurtimox (NECT) reduces the dose time to 1 week but still requires intravenous (i.v.) dosing (35).Antigenic variation is frequent, rendering prospects for vaccine development impracticable (22,27). What is urgently needed is a safe, orally (p.o.) administered drug, effective against both stages 1 and 2 of HAT, which then eliminates the need for staging and raises the potential for the eradication of sleeping sickness. Toward this aspiration, we have identified a class of boron-containing compounds, oxaborole carboxamides, as novel leads that show potent and selective trypanocidal activity in vitro. Two examples chosen from this lead series are AN3520 and SCYX-6759. These compounds exhibit rapid,

6-Arylpyrazine-2-carboxamides: A New Core for Trypanosoma brucei Inhibitors

“…SCYX-7158 was identified as the lead candidate for development to an orally active drug for treatment of second-stage HAT (163). After successful conclusion of the preclinical programme (163)(164)(165), SCYX-7158 entered phase-I clinical evaluation in February 2012 (register number: NCT01533961).…”

“…Attempts to predict the future distribution of HAT and tsetse in the face of climate change (164) were limited by lack of a robust database for current infection and fly distributions, and it is clear that the impact of population growth and climate change will differ by region. Future modelling will benefit from the HAT Atlas, although better estimates of population growth and improved climate simulations will also be needed.…”

Linking Phenotype to Kinase: Identification of a Novel Benzoxaborole Hinge-Binding Motif for Kinase Inhibition and Development of High-Potency Rho Kinase Inhibitors

“…Compounds from this class have led to several clinical candidates as inhibitors of leucyl aminoacyl-tRNA synthetase for treating fungi (Rock et al, 2007) and Gram-negative bacteria (Hernandez et al, 2013). Other compounds are phosphodiesterase inhibitors used for treating atopic dermatitis (Freund et al, 2012) or trypanosome growth inhibitors (Nare et al, 2010) used for treating African sleeping sickness. Our initial interest in the (aminomethylphenoxy)benzoxaborole family was stimulated by the inhibition of cytokine secretion in Toll-like receptor-stimulated PBMCs (Fig.…”

Antiprotozoal compounds: state of the art and new developments

“…However, the regimen is rather difficult to apply: 400 mg/kg/day in four doses for 14 days. Oxaboroles, also investigated for their use in VL, showed activity in animal models of T. brucei infection [63]. Some compounds, in particular SCYX-6759, cured murine CNS infection, however they were actively transported from the brain and had to be administered at high doses.…”

“…Further compounds investigated by the DNDi are oxaborole molecules from Anacor Pharmaceuticals [63] and nitroimidazole compounds from TB Alliance.…”