In vivo, in vitro and in silico methods for small molecule transfer across the BBB

The inability of molecules to permeate the BBB is a significant source of attrition in Central Nervous System (CNS) drug discovery. Given the increasing medical drivers for new and improved CNS drugs, small molecule transfer across the BBB is attracting a heightened awareness within pharmaceutical industry and medical fields. In order to assess the potential for small CNS molecules to permeate the BBB, a variety of methods and models, from in silico to in vivo going through in vitro models are developed as predictive tools in drug discovery. This review gives a comprehensive overview of different approaches currently considered in drug discovery to circumvent the lack of small molecule transfer through the BBB, together with their inherent advantages and disadvantages. Particularly, special attention is drawn to in silico models, with a detailed and contemporary point of view on prediction tools and guidelines for rational design. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4429-4468, 2009