Author/Authors :
Thomas A. Kirkland، نويسنده , , Marc Adler، نويسنده , , John G. Bauman، نويسنده , , Ming Chen، نويسنده , , Jesper Z. Haeggstr?m، نويسنده , , Beverly King، نويسنده , , Monica J. Kochanny، نويسنده , , Amy M. Liang، نويسنده , , Lisa Mendoza، نويسنده , , Gary B. Phillips، نويسنده , , Marjolein Thunnissen، نويسنده , , Lan Trinh، نويسنده , , Marc Whitlow، نويسنده , , Bin Ye، نويسنده , , Hong Ye، نويسنده , , John Parkinson، نويسنده , , William J. Guilford، نويسنده ,
Abstract :
Leukotriene B4 (LTB4) 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 LTB4 and possibly identify novel treatments, inhibitors of the LTB4 biosynthetic enzyme, leukotriene A4 hydrolase (LTA4-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA4-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.
