Leveraging Kinase Drugs for Neurosciences: Discovery of Selective, CNS-Penetrant Reversible Bruton's Tyrosine Kinase Inhibitors as Therapeutics for Neuroinflammation.

As a result, a retrospective analysis showed that the majority of the compounds occupied a narrow range of CNS MPO scores ( Figures and a, 75% between 1.5 and 2.5), and utilizing CNS MPO scores to triage compounds for screening resulted in numerous false negatives as the calculated scores did not correlate with the data observed in the in vitro MDCK and in vivo K p,uu assays ( Figure c–e). On the other hand, and contrary to the initial results observed in the benzazepine series, a strong trend was observed with the tolyl series ( Figure b) between the in vitro MDCK assay and in vivo K p,uu , with 75% of compounds with in vitro ER < 3 demonstrating K p,uu > 0.3 in vivo ( Figure d,e).

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