Synthesis and structure-activity relationship of acylthiourea derivatives as inhibitors of microsomal epoxide hydrolase

Abstract

Microsomal epoxide hydrolase (mEH) is a liver enzyme involved in hepatic and extrahepatic metabolism of xenobiotics, namely, the hydrolysis of epoxides and arene oxides to the corresponding diols. In some cases, the action of mEH activates xenobiotics, such as 7,12-dimethylbenz[ a]anthracene, potentiating their ability to induce mammary, ovarian, skin, and other types of cancer according to Rajapaksa et al. (Toxicol. Sci 96:327-334, 2006). Similarly, mEH polymorphisms have been linked to several types of cancer as stated by Benhamou et al. (Cancer Res. 58:5291-5293, 1998), and also to emphysema according to Smith and Harrison (Lancet 350:630-633, 1997). mEH inhibitors would provide insight into the multiple roles of this enzyme and potentially have clinical relevance for preventing disease in high-risk individuals. In this article, we describe the design and synthesis of acylthiourea analogs as inhibitors of mEH.