Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A sub(4) hydrolase

Leukotriene B sub(4) (LTB sub(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB sub(4) and possibly identify novel treatments, inhibitors of the LTB sub(4) biosynthetic enzyme, leukotriene A sub(4) hydrolase (LTA sub(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA sub(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.