Rapid synthesis of an array of trisubstituted urea-based soluble epoxide hydrolase inhibitors facilitated by a novel solid-phase method.
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.
Kowalski
Jennifer A
JA
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. jennifer.kowalski@boehringer-ingelheim.com
Swinamer
Alan D
AD
Muegge
Ingo
I
Eldrup
Anne B
AB
Kukulka
Alison
A
Cywin
Charles L
CL
De Lombaert
Stéphane
S
D000818:Animals; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000138:chemical synthesis*; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry
D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D014508:Urea; D004851:Epoxide Hydrolases