Decreasing the CYP2D6 contribution to metabolism of a CK1ε inhibitor

[Display omitted] •Our CK1epsilon inhibitors were metabolized by CYP2D6, a highly polymorphic enzyme.•Goal was to reduce contribution from CYP2D6 and maintain activity towards CK1epsilon.•Data analysis lead to understanding of structure-metabolism for the series towards CYP2D6.•Further modeling using previous methods were predictive.•Subsequent modification provided a compound with good CK1epsilon activity and no CYP2D6 contribution. Our internal casein kinase 1ε lead inhibitor, compound 1 was partially cleared by the polymorphic cytochrome P450 2D6. CYP2D6 involvement in metabolism implies more extensive clinical trials. We therefore wanted to reduce the contribution to clearance by this enzyme. We utilized metabolism reports for compound 1 performed in recombinant CYP2D6 together with structure-metabolism variation in structures of closely related analogs in order to see if we could incorporate similar substitution patterns in our lead compound. In addition, we utilized a previously established docking method using a modified CYP2D6 crystal structure to see if the metabolism patterns in CYP2D6 could be reproduced to afford the metabolites in the metabolism reports as well as those for the compounds used in the structure-metabolism relationship. All three of these steps, the metabolism report, the establishment of structure-metabolism relationships and the docking, lead to compound 10 where CYP2D6 was not involved in the clearance pathways.