Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 50, Issue 21, Pages 5217-5226Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm070705c
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Funding
- NHLBI NIH HHS [R01 HL059699-06A1, R01 HL059699, R01 HL59699-06A1] Funding Source: Medline
- NIEHS NIH HHS [P42 ES004699-21, P30 ES005707, P42 ES04699, R37 ES002710-27, P42 ES004699, R37 ES002710, R37 ES02710, P30 ES05707, P30 ES005707-119017] Funding Source: Medline
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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.
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