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

Kirkland, Thomas A.; Adler, Marc; Bauman, John G.; Chen, Ming; Haeggstrom, Jesper Z.; King, Beverly; Kochanny, Monica J.; Liang, Amy M.; Mendoza, Lisa and Phillips, Gary B., et al. (2008) In Bioorganic & Medicinal Chemistry 16(9). p.4963-4983
Abstract
Leukotriene B-4 (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 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... (More)
Leukotriene B-4 (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 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. (Less)
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publication status
published
subject
keywords
leukotriene A4, inhibitor, crystal structure
in
Bioorganic & Medicinal Chemistry
volume
16
issue
9
pages
4963 - 4983
publisher
Elsevier
external identifiers
  • wos:000255605600015
  • scopus:43049122101
ISSN
0968-0896
DOI
10.1016/j.bmc.2008.03.042
language
English
LU publication?
yes
id
17c10e73-351e-419a-a3f9-aaa56a7bfdae (old id 1204911)
date added to LUP
2008-09-18 11:33:44
date last changed
2017-01-01 04:37:26
@article{17c10e73-351e-419a-a3f9-aaa56a7bfdae,
  abstract     = {Leukotriene B-4 (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 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.},
  author       = {Kirkland, Thomas A. and Adler, Marc and Bauman, John G. and Chen, Ming and Haeggstrom, Jesper Z. and King, Beverly and Kochanny, Monica J. and Liang, Amy M. and Mendoza, Lisa and Phillips, Gary B. and Thunnissen, Marjolein and Trinh, Lan and Whitlow, Marc and Ye, Bin and Ye, Hong and Parkinson, John and Guilford, William J.},
  issn         = {0968-0896},
  keyword      = {leukotriene A4,inhibitor,crystal structure},
  language     = {eng},
  number       = {9},
  pages        = {4963--4983},
  publisher    = {Elsevier},
  series       = {Bioorganic & Medicinal Chemistry},
  title        = {Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase},
  url          = {http://dx.doi.org/10.1016/j.bmc.2008.03.042},
  volume       = {16},
  year         = {2008},
}