1,3-disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties.
Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.
Kim
In-Hae
IH
Department of Entomology and University of California Davis Cancer Center, University of California, One Shields Avenue, Davis, California 95616, USA.
Tsai
Hsing-Ju
HJ
Nishi
Kosuke
K
Kasagami
Takeo
T
Morisseau
Christophe
C
Hammock
Bruce D
BD
D000218:Adamantane / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D003510:Cyclohexanes; D010671:Phenylurea Compounds; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane