Assessment of pharmacokinetic properties in early drug discovery: evaluation of promising antitrypanosoma compounds and hit-to-lead optimization

Abstract

The current available treatmentfor Chagas' disease is poorly effective during the chronic phase, is relatively toxic and long-lasting. In the search for a more tolerable, effective and affordable drug to the patientsthe LINS03 series has been developed by our group during the past five years as antiparasitic agents, and to datemore than 50 compounds have already been synthesized and evaluated. Among them, several analogues were considered promising lead candidates for further development, however the main focus was only givenon the pharmacodynamic point of view (i.e. efficacy), and problems with solubility were identified, which limit the potential efficacy in vivo. Considering this scenario, this project proposes in vitroevaluations of the LINS03 compounds at theDMPK facility of University of Dundee (Drug Discovery Unit), to obtain structural information on these compounds to guide the design of improved compounds with high efficacy against T. cruzi.The evaluation of the solubility on relevant conditions, lipophilicity, permeability on PAMPA models, plasma protein binding and stability on plasma and hepatic microsomes will be carried out. The results will certainly provide important information to be considered in the design of novel compounds but also to select the most promising for further in vivo evaluation. (AU)