Evaluation of ADME parameters early in the discovery process is widely used during target validation, hit-discovery, hit-to-lead optimisation stages. We have developed a platform that allows to evaluate these parameters rapidly.
PK in rodents. We have decided to help further medicinal chemists in their optimisation efforts and to provide as early as possible project leaders with the relevant information to select the best compounds for in vivo experiments and to interpret in vivo data collected on the model. In our organisation, only compounds with relevant pharmacokinetic (Cmax, and clearance) will be administered to animal model. This is the only way to understand the phenotypic and biological observations made on the animal. It will also save animal lives, since only compounds that could realistically reach the target compartment and last long enough there will be administered. Last but not least, together with in vitro PK data (plasma and microsomal stability, solubility...) these early in vivo data will drive the optimisation of the lead structure toward the best possible in vivo performance.
Early formulation. Before the administration to an animal, an adequate formulation of the active ingredient (i.e. controlled modification of its physical state, preparation of a suspension or a suspension in a suitable solvent) needs to be carefully performed to ensure reliability and reproducibility of in vivo results. In collaboration with Juergen Siepmann, professor of pharmaceutical sciences (“pharmacie galénique”) in Lille, we have obtained a grant from Région Nord-Pas-de-Calais, to set up a platform for early formulation. By e-formulation we mean rapid and miniaturized formulation, adapted to molecules not yet fully optimized and to an administration of minute quantities to small animals (mice in particular). The animal experimentation take place in the animal facilities of the Pasteur Institute of Lille. Sample preparation and bioanalysis are performed by an engineer using our LC-MSMS platform.
In silico tools. Software tools are developed to calculate parameters in silico and predict bioavailability (Pipeline PilotTM or Chem AxonTM).
Montaigne, D., Marechal, X., Modine, T., Coisne, A., Mouton, S., Fayad, G., Ninni, S., Klein, C., Ortmans, S., Seunes, C., Potelle, C., Berthier, A., Gheeraert, C., Piveteau, C., Deprez-Poulain, R., Eeckhoute, J., Duez, H., Lacroix, D., Deprez, B., Jegou, B., Koussa, M., Edme, J. L., Lefebvre, P., & Staels, B. Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbalpha antagonism: a single-centre propensity-matched cohort study and a randomised study. Lancet,2017 391(10115): 59–69 .10.1016/s0140-6736(17)32132-3
Hermant, P., Bosc, D., Piveteau, C., Gealageas, R., Lam, B. V., Ronco, C., Roignant, M., Tolajanahary, H., Jean, L., Renard, P.-Y., Lemdani, M., Bourotte, M., Herledan, A., Bedart, C., Biela, A., Leroux, F., Deprez, B., & Deprez-Poulain, R. Controlling Plasma Stability of Hydroxamic Acids: A MedChem Toolbox. Journal of Medicinal Chemistry,2017, 60(21): 9067–9089. 10.1021/acs.jmedchem.7b01444