Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

Edward G. McIver; Justin Bryans; Kristian Birchall; Jasveen Chugh; Thomas Drake; Stephen J. Lewis; Joanne Osborne; Ela Smiljanic-Hurley; William Tsang; Ahmad Kamal; Alison Levy; Michelle Newman; Debra Taylor; J. Simon C. Arthur; Kristopher Clark; Philip Cohen

doi:10.1016/j.bmcl.2012.09.063

Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

Edward G. McIver
, Justin Bryans
, Kristian Birchall
, Jasveen Chugh
, Thomas Drake
, Stephen J. Lewis
, Joanne Osborne
, Ela Smiljanic-Hurley
, William Tsang
, Ahmad Kamal
, Alison Levy
, Michelle Newman
, Debra Taylor
, J. Simon C. Arthur
, Kristopher Clark
, Philip Cohen

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

39 Scopus citations

Abstract

The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

Original language	English
Pages (from-to)	7169-7173
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2012.09.063
State	Published - 1 Dec 2012
Externally published	Yes

Keywords

IKKε
Interferon β
IκB kinase epsilon
RANTES
TANK-binding kinase
TBK1

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10.1016/j.bmcl.2012.09.063

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McIver, E. G., Bryans, J., Birchall, K., Chugh, J., Drake, T., Lewis, S. J., Osborne, J., Smiljanic-Hurley, E., Tsang, W., Kamal, A., Levy, A., Newman, M., Taylor, D., Arthur, J. S. C., Clark, K., & Cohen, P. (2012). Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases. Bioorganic and Medicinal Chemistry Letters, 22(23), 7169-7173. https://doi.org/10.1016/j.bmcl.2012.09.063

@article{aa55150fec8e4f8aba65abd709ef8a51,

title = "Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases",

abstract = "The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.",

keywords = "IKKε, Interferon β, IκB kinase epsilon, RANTES, TANK-binding kinase, TBK1",

author = "McIver, \{Edward G.\} and Justin Bryans and Kristian Birchall and Jasveen Chugh and Thomas Drake and Lewis, \{Stephen J.\} and Joanne Osborne and Ela Smiljanic-Hurley and William Tsang and Ahmad Kamal and Alison Levy and Michelle Newman and Debra Taylor and Arthur, \{J. Simon C.\} and Kristopher Clark and Philip Cohen",

year = "2012",

month = dec,

day = "1",

doi = "10.1016/j.bmcl.2012.09.063",

language = "English",

volume = "22",

pages = "7169--7173",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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}

McIver, EG, Bryans, J, Birchall, K, Chugh, J, Drake, T, Lewis, SJ, Osborne, J, Smiljanic-Hurley, E, Tsang, W, Kamal, A, Levy, A, Newman, M, Taylor, D, Arthur, JSC, Clark, K & Cohen, P 2012, 'Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases', Bioorganic and Medicinal Chemistry Letters, vol. 22, no. 23, pp. 7169-7173. https://doi.org/10.1016/j.bmcl.2012.09.063

TY - JOUR

T1 - Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

AU - McIver, Edward G.

AU - Bryans, Justin

AU - Birchall, Kristian

AU - Chugh, Jasveen

AU - Drake, Thomas

AU - Lewis, Stephen J.

AU - Osborne, Joanne

AU - Smiljanic-Hurley, Ela

AU - Tsang, William

AU - Kamal, Ahmad

AU - Levy, Alison

AU - Newman, Michelle

AU - Taylor, Debra

AU - Arthur, J. Simon C.

AU - Clark, Kristopher

AU - Cohen, Philip

PY - 2012/12/1

Y1 - 2012/12/1

N2 - The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

AB - The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.

KW - IKKε

KW - Interferon β

KW - IκB kinase epsilon

KW - RANTES

KW - TANK-binding kinase

KW - TBK1

UR - https://www.scopus.com/pages/publications/84869093852

U2 - 10.1016/j.bmcl.2012.09.063

DO - 10.1016/j.bmcl.2012.09.063

M3 - Article

C2 - 23099093

AN - SCOPUS:84869093852

SN - 0960-894X

VL - 22

SP - 7169

EP - 7173

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases

Abstract

Keywords

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