Referenced in: none

Automatically associated channels: Kv11.1

Title: An in situ oxidation strategy towards overcoming hERG affinity.

Authors: David C Pryde, Rhys Jones, Donald S Middleton, Ben J Laverty, David R Fenwick, Helen J Mason, Martin Corless, Nick N Smith

Journal, date & volume: Bioorg. Med. Chem. Lett., 2010 Nov 15 , 20, 6400-4

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20934332

Abstract
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.