Identification of benzofuran central cores for the inhibition of leukotriene A(4) hydrolase.
Eccles W, Blevitt JM, Booker JN, Chrovian CC, Crawford S, de Leon AR, Deng X, Fourie AM, Grice CA, Herman K, Karlsson L, Kearney AM, Lee-Dutra A, Liang J, Luna R, Pippel D, Rao N, Riley JP, Santillán A, Savall B, Tanis VM, Xue X, Young AL.
Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).