title: Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.
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.
authors.affiliation: Department of Medicinal Chemistry, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94804, United States. Thomas.kirkland@promega.com
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kirkland
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: John G
authors.initials: JG
authors.lastname: Bauman
authors.forename: Ming
authors.initials: M
authors.lastname: Chen
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
authors.forename: Beverly
authors.initials: B
authors.lastname: King
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Kochanny
authors.forename: Amy M
authors.initials: AM
authors.lastname: Liang
authors.forename: Lisa
authors.initials: L
authors.lastname: Mendoza
authors.forename: Gary B
authors.initials: GB
authors.lastname: Phillips
authors.forename: Marjolein
authors.initials: M
authors.lastname: Thunnissen
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.forename: William J
authors.initials: WJ
authors.lastname: Guilford
mesh_terms: 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
chemical_list: D018698:Glutamic Acid; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase