Invited Speaker

The Challenges of the CNS Medicinal Chemist, the Traps to Avoid
Pascal George
France

The major challenges of the medicinal chemist resides in the optimization process of drugs being multi-parameters. This includes trans-epithelial permeation, metabolic stability, CYP inhibition and induction, HERG, safety in general. Some prototypic situations will be given as illustrative examples. For the CNS medicinal chemist blood brain barrier (BBB) permeation still remains an additional challenge. In vitro tools are available for evaluating at an early stage the BBB permeation properties of drugs. Of particular interest is the in vitro model consisting of a mono-layer of co-cultured endothelial cells, in presence of astrocytes that allows the evaluation of trans-endothelial permeability properties. This model is useful but presents some drawbacks and limitations. In addition it cannot be taken isolated from others PK parameters for optimizing in vivo BBB permeation properties. Illustration of prototypic cases will be presented, including false positive or negative results, matched and mismatched relations between in vitro and in vivo results. Alternative tests including evaluation of efflux effects may be also useful. As a conclusion: BBB permeation properties have to be linked to metabolic stability, oral absorption and in vivo PK parameters for ideal optimization of CNS drugs.