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.
authors.affiliation: MRC Technology, Centre for Therapeutics Discovery, 1-3 Burtonhole Lane, Mill Hill, London, NW7 1AD, UK. emciver@tech.mrc.ac.uk
authors.forename: Edward G
authors.initials: EG
authors.lastname: McIver
authors.forename: Justin
authors.initials: J
authors.lastname: Bryans
authors.forename: Kristian
authors.initials: K
authors.lastname: Birchall
authors.forename: Jasveen
authors.initials: J
authors.lastname: Chugh
authors.forename: Thomas
authors.initials: T
authors.lastname: Drake
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lewis
authors.forename: Joanne
authors.initials: J
authors.lastname: Osborne
authors.forename: Ela
authors.initials: E
authors.lastname: Smiljanic-Hurley
authors.forename: William
authors.initials: W
authors.lastname: Tsang
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kamal
authors.forename: Alison
authors.initials: A
authors.lastname: Levy
authors.forename: Michelle
authors.initials: M
authors.lastname: Newman
authors.forename: Debra
authors.initials: D
authors.lastname: Taylor
authors.forename: J Simon C
authors.initials: JS
authors.lastname: Arthur
authors.forename: Kristopher
authors.initials: K
authors.lastname: Clark
authors.forename: Philip
authors.initials: P
authors.lastname: Cohen
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; C579675:BX795; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D051550:I-kappa B Kinase