Further development of our Drug Discovery Platform FORECASTER and its application to the design, synthesis and biological evaluation of prolyl oligopeptidase Inhibitors

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Prolyl Oligopeptidase (POP) inhibition is a highly promising strategy for the treatment of Alzheimer's disease and POP inhibitors as drug candidates are to be developed. Moitessier and co-workers have recently reported a potent, permeant and highly selective POP inhibitor. However, its stability and pharmacokinetic profile need to be improved. A large number of drug discovery and development projects fail at the late development stages due to poor pharmacokinetic profiles. Integrating the evaluation of absorption, distribution, metabolism, excretion and toxicity (ADME-Tox) of potential candidate drugs early in the drug discovery process is expected to significantly reduce this failure rate. IIi this context, predicting the ADME-Tox profile using computational methods has been seen as a high-throughput and inexpensive option that could complement low to medium throughput in vitro or in vivo assays. Moitessier and co-workers have developed a sophisticated platform of programs (FORECASTER) which performs virtual screening, docking and more (www.fitted.ca). In this research, we plan to combine our complementary expertise in organic synthesis, medicinal chemistry, metabolism and software development to 1. develop accurate in silico methods that predict the cytochrome P450-mediated metabolism and P450 inhibition and implement them in our platform FORECASTER; 2. apply this suite of programs to the development of improved POP inhibitors.