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

  • Bioorg Med Chem Lett. 2012 Dec 1;22(23):7169-73. doi: 10.1016/j.bmcl.2012.09.063.
Edward G McIver  1 ,  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
Affiliations
  • 1. MRC Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK. [email protected]
PMID: 23099093 DOI: 10.1016/j.bmcl.2012.09.063
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.

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