Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy

We
designed and synthesized perhexiline analogues that have the same
therapeutic profile as the parent cardiovascular drug but lacking
its metabolic liability associated with CYP2D6 metabolism. Cycloalkyl
perhexiline analogues 6a–j were found
to be unsuitable for further development, as they retained a pharmacokinetic
profile very similar to that shown by the parent compound. Multistep
synthesis of perhexiline analogues incorporating fluorine atoms onto
the cyclohexyl ring(s) provided a range of different fluoroperhexiline
analogues. Of these, analogues 50 (4,4-gem-difluoro) and 62 (4,4,4′,4′-tetrafluoro)
were highly stable and showed greatly reduced susceptibility to CYP2D6-mediated
metabolism. In vitro efficacy studies demonstrated that a number of
derivatives retained acceptable potency against CPT-1. Having the
best balance of properties, 50 was selected for further
evaluation. Like perhexiline, it was shown to be selectively concentrated
in the myocardium and, using the Langendorff model, to be effective
in improving both cardiac contractility and relaxation when challenged
with high fat buffer.