Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.
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.
Kirkland
Thomas A
TA
Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. Thomas.kirkland@promega.com
Adler
Marc
M
Bauman
John G
JG
Chen
Ming
M
Haeggström
Jesper Z
JZ
King
Beverly
B
Kochanny
Monica J
MJ
Liang
Amy M
AM
Mendoza
Lisa
L
Phillips
Gary B
GB
Thunnissen
Marjolein
M
Trinh
Lan
L
Whitlow
Marc
M
Ye
Bin
B
Ye
Hong
H
Parkinson
John
J
Guilford
William J
WJ
D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018698:Glutamic Acid; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase