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

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36 Citations (Scopus)

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/IKKe pathway in inflammatory diseases.

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

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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 & Medicinal Chemistry Letters, 22(23), 7169-7173. https://doi.org/10.1016/j.bmcl.2012.09.063

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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/IKKe pathway in inflammatory diseases.",

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,

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

language = "English",

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journal = "Bioorganic & Medicinal Chemistry Letters",

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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 & 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

Y1 - 2012/12

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/IKKe 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/IKKe pathway in inflammatory diseases.

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U2 - 10.1016/j.bmcl.2012.09.063

DO - 10.1016/j.bmcl.2012.09.063

M3 - Article

SN - 0960-894X

VL - 22

SP - 7169

EP - 7173

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & 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

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