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

Chih-Chung Tseng, Hannah Noordali, Monica Sani, Melanie Madhani, Denis M. Grant, Michael Frenneaux, Matteo Zanda, Iain R. Greig

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Abstract

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. Multi-step synthesis of perhexiline analogues incorporating fluorine atoms onto the cyclohexyl ring(s) provided a range of different fluoro-perhexiline 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.
Original languageEnglish
Pages (from-to)2780-2789
Number of pages10
JournalJournal of Medicinal Chemistry
Volume60
Issue number7
Early online date9 Mar 2017
DOIs
Publication statusPublished - 13 Apr 2017

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