Daiichi Sankyo series

Despite intensive efforts, complete parasite clearance in the chronic model could be not achieved in vivo. This is likely to be associated with the specific mechanism of action behind T. cruzi parasite activity. The mechanism of action of the series has been elucidated with the assistance of our research collaborators, notably University of Dundee Drug Discovery Unit, Institut Pasteur Korea, and Griffith Institute for Drug Discovery. As complete parasite clearance in vivo could not be achieved and the mechanism of action of the series has been elucidated, this project has been recommended for termination.

Several newly synthetized compounds with enhanced pharmacokinetic profiles continued to be evaluated in vivo for efficacy in acute and chronic Chagas disease models at the London School of Hygiene & Tropical Medicine. Exploratory studies also continued at Swiss Tropical and Public Health Institute, University of Dundee Drug Discovery Unit, Institut Pasteur Korea, and Griffith Institute for Drug Discovery to elucidate the mechanism of action of the series and evaluate whether a complete parasite clearance can be achieved with this series both in vitro and in vivo.

The frontrunning series that is the current focus of this hit-to-lead project has clear activity against the T. cruzi parasite and will be progressed for Chagas disease.

The project milestone was reached with the identification of a progressable Chagas lead series with proven in vivo efficacy. Daiichi Sankyo and DNDi are now looking for funding to progress this promising series for Chagas disease in 2019.

Three T. cruzi active series with marginal activity against Leishmania were identified from a high-throughput screening of 40,000 members of the Daiichi Sankyo Pharma Space Library. Current medicinal chemistry efforts of this hit-to-lead collaboration focus on one series that was confirmed as the most promising chemotype in terms of activity and selectivity profile. To date, over 100 analogs to this series have been synthesized and tested for T. cruzi  and Leishmania activities at Institut Pasteur Korea, leading to the identification of four preferred molecules nominated to proceed with pharmacokinetics studies. This project was initiated in April 2017 for a duration of 18 months.