Targeting protein kinases in central nervous system disorders

The success of drugs such as imatinib has made protein kinases an intensively studied class of drug targets.Research on new protein kinase targets and a range of potential disease indications has led to increasing interest in the development of small-molecule kinase inhibitors for the treatment of central nervous system (CNS) disorders.Although disclosed clinical trial information shows a current oncology focus to CNS clinical investigations, preclinical in vivo studies of protein kinase inhibitors in animal models reveal a major increase in efforts for other CNS disease indications. Selected examples of emerging protein kinase targets for CNS disorders and the state of inhibitor development are discussed in this Review.A crucial issue in CNS drug discovery is the challenge of effective blood–brain barrier (BBB) penetrance. Statistical analysis of a database of 448 disclosed small molecules revealed trends in molecular properties that correlate with in vivo BBB penetrance. Lower molecular weights and polar surface area values were correlated with brain uptake, whereas higher lipophilicity was not. The available information about CNS drug discovery in general, and kinase inhibitor drugs in particular, raises concerns about the approach of applying existing drugs to CNS therapeutic use.Some of the molecular property trends that correlate with good BBB penetrance also correlate with a molecule being a good substrate for the first-pass metabolism enzyme cytochrome P450 2D6 (CYP2D6). Polymorphisms in this enzyme contribute to variability between individuals in drug metabolism. In medicinal chemistry refinement to improve BBB penetrance, care must therefore be taken to avoid generating better CYP2D6 substrates. Currently, 31% of approved CNS drugs are metabolized by CYP2D6.Current CNS-targeted drug discovery programmes use contemporary approaches, such as molecular fragment expansion, that address these issues at the compound design stage and use early drug property and bioavailability screens to generate fewer, more CNS-focused lead compounds.