Pharmacokinetic and drug metabolism studies in drug discovery and development

Abstract

Cruzain (EC 3.4.22.51) is the major cysteine protease from Trypanosoma cruzi, the Chagas disease etiological agent. Due to its biological relevance, this enzyme is considered one of the most relevant targets to develop new anti-chagasics, which is urgent once the available therapy is old and very toxic due to a blend of unsatisfactory side effects and lack of efficacy. In this way, the student PhD project aims to identify new cruzain inhibitors based on the optimization of potency and selectivity of previous identified molecules (lead compounds). In order to deepen our understanding on the structure activity relationships (SAR), series of analogs were designed, synthesized and evaluated against cruzain and T. cruzi. A promising set of compounds was selected with IC50 values in the nano- and micro-molar range against cruzain and, in some cases, with activity against the parasite in micro-molar concentrations. To enrich this work, the present project proposes a scientific collaboration between the Laboratório de Química Medicinal e Computacional (LQMC) from University of São Paulo (USP) and the Drug Metabolism and Pharmacokinetics department at AbbVie - Pharmaceutical Research and Development. Research studies will focus on the identification of the pharmacokinetic profile of the compounds already identified in LQMC. This will allow us to optimize pharmacokinetic properties concomitantly with potency and selectivity for cruzain in a very first stage of drug design. These studies will contribute to the student's scientific background by allowing the contact and deepening the understanding of key concepts and state of the art methodologies in drug discovery. In addition, it is also important to highlight that this project resulted from a partnership promoted by DNDi - Drugs for Neglected Diseases initiative and will enable great advances in our research group, being a central part of our CIBFar, a CEPID-FAPESP. (AU)