With new chemical entities currently undergoing clinical development for human African trypanosomiasis (HAT), since 2012 the focus of screening and lead optimization efforts has been on identifying compounds to develop for VL and Chagas disease.
Many advances have been made during 2014. The first in vivo proof of concept for a new chemical class (VL series 12 – aminopyrazoles) from Pfizer was achieved in the early curative model of VL. A full lead optimization programme is now underway. Several compounds demonstrated excellent activity in vivo. Two advanced leads oxaboroles, DNDi-2166148 and DNDi-2310789, were identified and will be scaled up to enable exploratory toxicology studies, which could enable selection of one as an optimized lead for VL.
A programme is ongoing to identify nitroimidazole backups. Over 200 analogues have been prepared so far, and two backup compounds originating from different core structures have been selected and are being further profiled for in vivo efficacy and safety. Multiple hits from screening with several pharmaceutical partners or from other sources were progressed into hit confirmation and expansion studies. Several series have moved into the hit-to-lead stage for both Chagas disease and VL.
A number of pharmacokinetic and pharmacodynamic studies have been conducted in animal models of VL using existing and experimental drugs to build improved PK/PD models and ameliorate the translation of new drugs from discovery into clinical studies. In addition, a new screening cascade for Chagas disease has been implemented: the insight gained into the PK/PD relationship of compounds from additional in vitro assays coupled with a new in vivo model will enable compounds to be moved forward with more confidence.