Unsymmetrical non-adamantyl N,N'-diaryl urea and amide inhibitors of soluble expoxide hydrolase.
Incorporation of an adamantyl group in prototypical soluble expoxide hydrolase (sEH) inhibitors afforded improved enzyme potency. We explored replacement of the adamantyl group in unsymmetrical ureas and amides with substituted aryl rings to identify equipotent and metabolically stable sEH inhibitors. We found that aryl rings, especially those substituted in the para position with a strongly electron withdrawing substituent, afforded enzyme IC(50) values comparable to the adamantyl compounds in an ether substituted, unsymmetrical N,N'-diaryl urea or amide scaffold.
Anandan
Sampath-Kumar
SK
Arete Therapeutics, Inc., 3912 Trust Way, Hayward, CA 94545, USA. skumar@aretetherapeutics.com
Webb
Heather K
HK
Do
Zung N
ZN
Gless
Richard D
RD
D000577:Amides / Q000737:chemistry; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004583:Electrons; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005456:Fluorescent Dyes / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D015394:Molecular Structure; D012995:Solubility; D014508:Urea / Q000737:chemistry*
D000577:Amides; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D014508:Urea; D004851:Epoxide Hydrolases