An in situ oxidation strategy towards overcoming hERG affinity

In an effort to overcome hERG affinity with a lead compound, several S-oxide and N-oxide analogues were synthesised with a much improved hERG profile but low in vivo absorption. This led to the implementation of an in situ oxidation strategy wherein a sulfide was dosed orally and systemic levels of the corresponding sulfoxide and sulfone were monitored. SAR and pharmacokinetic data to support this as a possible strategy are presented, although ultimately the approach was shown not to be suitable due to very low levels of active circulating metabolites.

Graphical abstractA series of oxidised, for example, sulfoxide, CCR5 antagonists have been identified as highly potent with a large window over inhibition of the hERG channel, but with very low permeability and in vivo absorption. A strategy is described which involved dosing to rats a much more permeable sulfide precursor, which underwent in situ oxidation to the corresponding sulfoxide and sulfone. SAR, metabolism and pharmacokinetic data which underpinned this strategy is described.Figure optionsDownload full-size imageDownload as PowerPoint slide