Now showing 1 - 2 of 2
  • Publication
    Targeted Fluorination of a Non-steroidal Anti-inflammatory Drug to Prolong Metabolic Half-life
    In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug’s metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4′-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.
      382Scopus© Citations 19
  • Publication
    Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach
    Incorporation of fluorine in a drug can dramatically affect its metabolism and methods to assess the effect of fluorine substitution on drug metabolism are required for effective drug design. Employing a previously developed chemical-microbial method the metabolism of a series of fluorinated biphenyl ethers was determined. The substrates were synthesized via Ullmann-type condensation reactions between bromotoluene and fluorophenol. The ethers were incubated with the fungus Cunninghamella elegans, which oxidises xenobiotics in an analogous fashion to mammals, generating a number of hydroxylated biphenyl ethers and acids. The propensity of the fluorinated ring to be hydroxylated depended upon the position of the fluorine atom, and the oxidation of the methyl group was observed when it was meta to the oxygen. The experiments demonstrate the applicability of the method to rapidly determine the effect of fluorine substitution on CYP-catalysed biotransformation of pro-drug molecules.
    Scopus© Citations 7  357