CHAPTER 6: The Design of Brain Penetrant Kinase Inhibitors

The desire for brain penetrant kinase inhibitors has increased in recent years to enable the treatment of both primary and secondary brain tumours but also for the potential management of degenerative CNS diseases such as Alzheimer's and Parkinson's diseases. However, the design of compounds that are able to access the brain is a formidable challenge, exacerbated by the fact that traditional kinase inhibitor design space does not overlap well with the physicochemical properties of established CNS compounds. This chapter overviews the challenges facing kinase medicinal chemists and highlights progress to date, illustrating with a growing number of successful kinase inhibitor case histories where brain penetration has now been obtained and shown to drive in vivo CNS efficacy.