Development of fluorinated analogues of perhexiline with improved pharmacokinetic properties and retained efficacy

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Tseng, Chih-Chung, Noordali, Hannah, Sani, Monica, Madhani, Melanie, Grant, Denis M., Frenneaux, Michael P., Zanda, Matteo and Greig, Iain R. (2017) Development of fluorinated analogues of perhexiline with improved pharmacokinetic properties and retained efficacy. Journal of Medicinal Chemistry, 60 (7). 2780–2789. ISSN 0022-2623

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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. 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.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Cardiovascular and Metabolic Health
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Depositing User: Pure Connector
Date Deposited: 06 Apr 2017 07:00
Last Modified: 12 May 2023 03:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/63179
DOI: 10.1021/acs.jmedchem.6b01592

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