title: Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy.
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.
authors.affiliation: Kosterlitz Centre for Therapeutics, University of Aberdeen , Foresterhill, Aberdeen, AB25 2ZD, U.K.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Tseng
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham , Edgbaston, Birmingham, B15 2TT, U.K.
authors.forename: Hannah
authors.initials: H
authors.lastname: Noordali
authors.affiliation: C.N.R.-I.C.R.M. , Via Mancinelli 7, 20131 Milan, Italy.|KemoTech s.r.l. , Parco Scientifico della Sardegna, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Sani
authors.affiliation: Institute of Cardiovascular Sciences, University of Birmingham , Edgbaston, Birmingham, B15 2TT, U.K.
authors.forename: Melanie
authors.initials: M
authors.lastname: Madhani
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto , Toronto M5S 1A8, Canada.
authors.forename: Denis M
authors.initials: DM
authors.lastname: Grant
authors.affiliation: Kosterlitz Centre for Therapeutics, University of Aberdeen , Foresterhill, Aberdeen, AB25 2ZD, U.K.|Norwich Medical School, University of East Anglia , Norwich NR4 7UQ, U.K.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
authors.affiliation: Kosterlitz Centre for Therapeutics, University of Aberdeen , Foresterhill, Aberdeen, AB25 2ZD, U.K.|C.N.R.-I.C.R.M. , Via Mancinelli 7, 20131 Milan, Italy.
authors.forename: Matteo
authors.identifier: 0000-0002-8257-5232
authors.initials: M
authors.lastname: Zanda
authors.affiliation: Kosterlitz Centre for Therapeutics, University of Aberdeen , Foresterhill, Aberdeen, AB25 2ZD, U.K.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Greig
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D054879:Halogenation; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010480:Perhexiline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D002317:Cardiovascular Agents; D019389:Cytochrome P-450 CYP2D6; D010480:Perhexiline