The discovery of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta kinases.
A potent and selective series of 2-amino-3,5-diarylbenzamide inhibitors of IKK-alpha and IKK-beta is described. The most potent compounds are 8h, 8r and 8v, with IKK-beta inhibitory potencies of pIC(50) 7.0, 6.8 and 6.8, respectively. The series has excellent selectivity, both within the IKK family over IKK-epsilon, and across a wide variety of kinase assays. The potency of 8h in the IKK-beta enzyme assay translates to significant cellular activity (pIC(50) 5.7-6.1) in assays of functional and mechanistic relevance.
Christopher
John A
JA
GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. John.A.Christopher@gsk.com
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Barbara G
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Bamborough
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Champigny
Aurelie C
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Cutler
Geoffrey J
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D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006860:Hydrogen Bonding; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular
D001549:Benzamides; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase