An in situ oxidation strategy towards overcoming hERG affinity
David C Pryde1, Rhys Jones, Donald S Middleton
1Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. david.pryde@pfizer.com
Bioorganic & Medicinal Chemistry Letters
|October 12, 2010
Summary
Synthesizing S- and N-oxide analogues improved hERG affinity but reduced absorption. An in situ oxidation strategy was explored but failed due to insufficient active metabolites.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Pharmacokinetics
Background:
- Lead compounds often exhibit undesirable properties like hERG channel affinity.
- Oxidized analogues (S-oxides, N-oxides) can modify drug properties.
- In vivo absorption issues can hinder the development of promising drug candidates.
Purpose of the Study:
- To overcome hERG affinity issues in a lead compound.
- To evaluate the efficacy of an in situ oxidation strategy for drug delivery.
- To assess the structure-activity relationship (SAR) and pharmacokinetics of oxidized metabolites.
Main Methods:
- Synthesis of S-oxide and N-oxide analogues.
- Oral administration of a sulfide prodrug.
- Monitoring of systemic sulfoxide and sulfone metabolite levels.
- Pharmacokinetic and SAR analysis.
Main Results:
- Synthesized analogues showed improved hERG profiles but poor in vivo absorption.
- The in situ oxidation strategy resulted in very low levels of circulating active metabolites.
- The approach was ultimately deemed unsuitable for development.
Conclusions:
- While oxidized analogues can improve hERG profiles, absorption remains a challenge.
- In situ oxidation is not a viable strategy if active metabolites are not sufficiently absorbed.
- Further strategies are needed to balance hERG affinity and in vivo exposure.
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