Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

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Kirkland TA, Adler M, Bauman JG, Chen M, Haeggstrom JZ, King B, Kochanny MJ, Liang AM, Mendoza L, Phillips GB, Thunnissen M, Trinh L, Whitlow M, Ye B, Ye H, Parkinson J, Guilford WJ

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

Bioorg Med Chem. 2008 May 1;16(9):4963-83. doi: 10.1016/j.bmc.2008.03.042. Epub 2008 Mar 20.

PubMed ID

18394906 [ View in PubMed

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Abstract

Leukotriene B(4) (LTB(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(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2S)-2-amino-5-oxo-5-[(4-phenylmethoxyphenyl)amino]pentanoic acid	Leukotriene A-4 hydrolase	IC 50 (nM)	20	7.5	22	Details
4-amino-N-[4-(benzyloxy)phenyl]butanamide	Leukotriene A-4 hydrolase	IC 50 (nM)	61	7.5	22	Details
N-[4-(benzyloxy)phenyl]glycinamide	Leukotriene A-4 hydrolase	IC 50 (nM)	280	7.5	22	Details