Methodologies to Assess Drug Permeation Through the Blood-Brain Barrier for Pharmaceutical Research

ABSTRACT: The drug discovery process for drugs that target the central nervous system suffers from a very high rate of failure due to the presence of the blood-brain barrier, which limits the entry of xenobiotics into the brain. To minimise drug failure at different stages of the drug development process, new methodologies have been developed to understand the absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of drug candidates at early stages of drug development. Additionally, understanding the permeation of drug candidates is also important, particularly for drugs that target the central nervous system. During the first stages of the drug discovery process, in vitro methods that allow for the determination of permeability using high-throughput screening methods are advantageous. For example, performing the parallel artificial membrane permeability assay followed by cell-based models with interesting hits is a useful technique for identifying potential drugs. In silico models also provide interesting information but must be confirmed by in vitro models. Finally, in vivo models, such as in situ brain perfusion, should be studied to reduce a large number of drug candidates to a few lead compounds. This article reviews the different methodologies used in the drug discovery and drug development processes to determine the permeation of drug candidates through the blood-brain barrie

Prediction of passive blood-brain barrier permeability with PAMPA: from small molecules to complex formulations

Inappropriate pharmacokinetic has been recognized as being one of the major factors leading to the withdrawal of new chemical entities from drug development. Therefore, a large number of compounds has to be screened before matching one drug candidate disclosing good ADMET properties during the early stage of drug discovery. In vitro high throughput methods thus become tools of choice to assess compounds pharmacokinetics and in particular their ability to penetrate biological membranes such as the blood-brain barrier (BBB). This thesis aimed to develop a new in vitro high throughput artificial membrane able to predict passive transendothelial permeability of drug small molecules through the BBB with PAMPA. This new method was then applied to more complex matrices, such as the natural products and the nanotransporters, in order to understand their mode of permeation through the BBB and assess their impact on the central nervous system

Discovery of a novel class of potent coumarin monoamine oxidase B inhibitors

In an effort to discover novel selective monoamine oxidase (MAO) B inhibitors with favorable physicochemical and pharmacokinetic profiles, 7-[(m-halogeno)benzyloxy]coumarins bearing properly selected polar substituents at position 4 were designed, synthesized, and evaluated as MAO inhibitors. Several compounds with MAO-B inhibitory activity in the nanomolar range and excellent MAO-B selectivity (selectivity index SI > 400) were identified. Structure-affinity relationships and docking simulations provided valuable insights into the enzyme-inhibitor binding interactions at position 4, which has been poorly explored. Furthermore, computational and experimental studies led to the identification and biopharmacological characterization of 7-[(3-chlorobenzyl)oxy]-4-[(methylamino)methyl]-2H-chromen-2-one methanesulfonate 22b (NW-1772) as an in vitro and in vivo potent and selective MAO-B inhibitor, with rapid blood-brain barrier penetration, short-acting and reversible inhibitory activity, slight inhibition of selected cytochrome P450s, and low in vitro toxicity. On the basis of this preliminary preclinical profile, inhibitor 22b might be viewed as a promising clinical candidate for the treatment of neurodegenerative diseases