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

Thomas A. Kirkland; Marc Adler; John G. Bauman; Ming Chen; Jesper Z. Haeggstrom; Beverly King; Monica J. Kochanny; Amy M. Liang; Lisa Mendoza; Gary B. Phillips; Marjolein Thunnissen; Lan Trinh; Marc Whitlow; Bin Ye; Hong Ye; John Parkinson; William J. Guilford

doi:10.1016/j.bmc.2008.03.042

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

Thomas A. Kirkland, Marc Adler, John G. Bauman, Ming Chen, Jesper Z. Haeggstrom, Beverly King, Monica J. Kochanny, Amy M. Liang, Lisa Mendoza, Gary B. Phillips, Marjolein Thunnissen, Lan Trinh, Marc Whitlow, Bin Ye, Hong Ye, John Parkinson, William J. Guilford

Biochemistry and Structural Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	4963-4983
Journal	Bioorganic & Medicinal Chemistry
Volume	16
Issue number	9
DOIs	https://doi.org/10.1016/j.bmc.2008.03.042
Publication status	Published - 2008

Subject classification (UKÄ)

Biological Sciences

Free keywords

leukotriene A4
inhibitor
crystal structure

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10.1016/j.bmc.2008.03.042

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Kirkland, T. A., Adler, M., Bauman, J. G., Chen, M., Haeggstrom, J. Z., King, B., Kochanny, M. J., Liang, A. M., Mendoza, L., Phillips, G. B., Thunnissen, M., Trinh, L., Whitlow, M., Ye, B., Ye, H., Parkinson, J., & Guilford, W. J. (2008). Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase. Bioorganic & Medicinal Chemistry, 16(9), 4963-4983. https://doi.org/10.1016/j.bmc.2008.03.042

@article{17c10e73351e419aa3f9aaa56a7bfdae,

title = "Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase",

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.",

keywords = "leukotriene A4, inhibitor, crystal structure",

author = "Kirkland, {Thomas A.} and Marc Adler and Bauman, {John G.} and Ming Chen and Haeggstrom, {Jesper Z.} and Beverly King and Kochanny, {Monica J.} and Liang, {Amy M.} and Lisa Mendoza and Phillips, {Gary B.} and Marjolein Thunnissen and Lan Trinh and Marc Whitlow and Bin Ye and Hong Ye and John Parkinson and Guilford, {William J.}",

year = "2008",

doi = "10.1016/j.bmc.2008.03.042",

language = "English",

volume = "16",

pages = "4963--4983",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier",

number = "9",

}

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 2008, 'Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase', Bioorganic & Medicinal Chemistry, vol. 16, no. 9, pp. 4963-4983. https://doi.org/10.1016/j.bmc.2008.03.042

TY - JOUR

T1 - Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A(4) hydrolase

AU - Kirkland, Thomas A.

AU - Adler, Marc

AU - Bauman, John G.

AU - Chen, Ming

AU - Haeggstrom, Jesper Z.

AU - King, Beverly

AU - Kochanny, Monica J.

AU - Liang, Amy M.

AU - Mendoza, Lisa

AU - Phillips, Gary B.

AU - Thunnissen, Marjolein

AU - Trinh, Lan

AU - Whitlow, Marc

AU - Ye, Bin

AU - Ye, Hong

AU - Parkinson, John

AU - Guilford, William J.

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

KW - leukotriene A4

KW - inhibitor

KW - crystal structure

U2 - 10.1016/j.bmc.2008.03.042

DO - 10.1016/j.bmc.2008.03.042

M3 - Article

C2 - 18394906

SN - 0968-0896

VL - 16

SP - 4963

EP - 4983

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 9

ER -

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

Abstract

Subject classification (UKÄ)

Free keywords

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