Targeted fluorination of a nonsteroidal 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.
Department of Chemistry, Durham University, South Road, Durham DH1 3LE (UK).
Maxwell J
MJ
Shaughnessy
Antal
A
Harsanyi
Jingji
J
Li
Tara
T
Bright
Cormac D
CD
Murphy
Graham
G
Sandford
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D020093:Cunninghamella / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D005461:Fluorine / Q000737:chemistry / Q000378:metabolism*; D005480:Flurbiprofen / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006845:Hydrocarbons, Fluorinated; D005461:Fluorine; D005480:Flurbiprofen
cross-coupling reactions; cytochrome P450s; drug design; drug metabolism; fluorine