Rapid synthesis of an array of trisubstituted urea-based soluble epoxide hydrolase inhibitors facilitated by a novel solid-phase method

Jennifer A Kowalski; Alan D Swinamer; Ingo Muegge; Anne B Eldrup; Alison Kukulka; Charles L Cywin; Stéphane De Lombaert

doi:10.1016/j.bmcl.2010.04.078

Rapid synthesis of an array of trisubstituted urea-based soluble epoxide hydrolase inhibitors facilitated by a novel solid-phase method

Bioorg Med Chem Lett. 2010 Jun 15;20(12):3703-7. doi: 10.1016/j.bmcl.2010.04.078. Epub 2010 Apr 22.

Authors

Jennifer A Kowalski¹, Alan D Swinamer, Ingo Muegge, Anne B Eldrup, Alison Kukulka, Charles L Cywin, Stéphane De Lombaert

Affiliation

¹ Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. jennifer.kowalski@boehringer-ingelheim.com

PMID: 20472432
DOI: 10.1016/j.bmcl.2010.04.078

Abstract

A 270-membered library of trisubstituted ureas was synthesized and evaluated for inhibition of soluble epoxide hydrolase. Library design and reagent selection was guided by the use of a pharmacophore model and synthesis of the array was enabled with a general solid-phase method. This array approach facilitated multi-dimensional SAR around this series and identified functionality responsible for binding affinity, as well as opportunities for modulating the overall in vitro profiles of this class of soluble epoxide hydrolase inhibitors.

MeSH terms

Animals
Combinatorial Chemistry Techniques / methods*
Enzyme Inhibitors / chemical synthesis*
Epoxide Hydrolases / antagonists & inhibitors*
Humans
Protein Binding
Small Molecule Libraries / chemical synthesis*
Solubility
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemistry

Substances

Enzyme Inhibitors
Small Molecule Libraries
Urea
Epoxide Hydrolases