Targeted Fluorination of a Nonsteroidal Anti‐inflammatory Drug to Prolong Metabolic Half‐Life

Abstract

(2014) 'Targeted uorination of a nonsteroidal anti-in ammatory drug to prolong metabolic half-life.', ChemMedChem., 9 (4). pp. 733-736. Further information on publisher's website: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details.

Making Methods Rugged for Regulated Bioanalysis

“…The use of deuterium can also have the unintended consequence of imparting stability to the label that the analyte does not have [96]. Unlike a 13 C, 15 N or 18 O isotope, primary and secondary kinetic isotope effects using deuterium can be significant.…”

Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans

“…However, no The site of fluorine substitution had an influence on the extent of oxidation; thus compound 2, in which the fluorine is at C-3', was almost entirely biotransformed after 24 h incubation with C. elegans, whereas compound 3 (fluorine at C-2') was biotransformed to a much lesser degree and compound 4 (fluorine at C-4') was not biotransformed at all. Based on our previous studies with the related substrates fluorobiphenyl Murphy, 2010, Bright et al, 2013) and flurbiprofen , Shaughnessy et al, 2014, the 4' position is predominantly hydroxylated and if replaced with fluorine, no hydroxylation is observed, which would account for the absence of hydroxylation of 4. Furthermore, 2, 3 and 5 were similarly regiospecifically hydroxylated at C4' by the fungus.…”

“…Our previous studies on biphenyl systems , Bright et al, 2013, Shaughnessy et al, 2014 demonstrated that the hydroxylation typically occurs on the 4' (para) position. Furthermore, when this site is blocked by fluorine, no hydroxylation occurs, and the observation that 4 was not biotransformed by the fungus is consistent with this.…”

“…They also have enzymes associated with phase II (conjugative) metabolism, such as sulfotransferase, glucosyl transferase and glutathione S-transferase (Zhang et al, 1996). Furthermore, C. elegans can be employed in the design of fluorinated drugs, by identifying through biotransformation metabolically labile sites on non-fluorinated drug leads, which can then be modified by synthesis to contain fluorine at that specific position, thereby prolonging metabolic half-life (Bright et al, 2013, Shaughnessy et al, 2014. Amongst the many xenobiotics that Cunninghamella spp.…”

Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor

“…This is beneficial because of the rather limited space in the S 1 ′ pocket. The para ‐fluorinated compound was of highest interest to us, as it does not display a hydrogen atom in the para position, which is prone to metabolic degradation by cytochrome P450 enzymes . Driven by the promising results derived from the molecular design approach, we synthesized compounds 2 a – g (Figure ) in order to test our hypotheses with biological inhibitory data (Table ).…”