Designing drugs optimized for both blood–brain barrier permeation and intra-cerebral partition

INTRODUCTION: With the increasing incidence and prevalence of neurological disorders globally, there is a paramount need for new pharmacotherapies. BBB effectively protects the brain but raises a profound challenge to drug permeation, with less than 2% of most drugs reaching the CNS. AREAS COVERED: This article reviews aspects of the most recent design strategies, providing insights into ideas and concepts in CNS drug discovery. An overview of the products available on the market is given and why clinical trials are continuously failing is discussed. EXPERT OPINION: Among the available CNS drugs, small molecules account for most successful CNS therapeutics due to their ability to penetrate the BBB through passive or carrier-mediated mechanisms. The development of new CNS drugs is very difficult. To date, there is a lack of effective drugs for alleviating or even reversing the progression of brain diseases. Particularly, the use of artificial intelligence strategies, together with more appropriate animal models, may enable the design of molecules with appropriate permeation, to elicit a biological response from the neurotherapeutic target.