The identification of potent and selective imidazole-based inhibitors of B-Raf kinase Andrew K. Takle, a, * Murray J. B. Brown, b Susannah Davies, a David K. Dean, a Gerraint Francis, a Alessandra Gaiba, a Alex W. Hird, a Frank D. King, a Peter J. Lovell, a Antoinette Naylor, a Alastair D. Reith, c Jon G. Steadman a and David M. Wilson a a Department of Medicinal Chemistry, Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK b Department of Screening and Compound Profiling, GlaxoSmithKline Pharmaceuticals, Medicines R&D Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK c Department of High Throughput Biology, GlaxoSmithKline Pharmaceuticals, Medicines R&D Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK Received 28 July 2005; revised 23 September 2005; accepted 28 September 2005 Available online 2 November 2005 Abstract—A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase. Ó 2005 Elsevier Ltd. All rights reserved. Mitogen-activated protein (MAP) kinases are a family of serine/threonine protein kinases that participate in signal transduction pathways controlling numerous intra-cellular events. 1 MAP kinases are regulated by phosphorylation cascades whereby activation of an up- stream kinase leads to phosphorylation of a downstream substrate which itself has protein kinase activity. Typi- cally in such MAP kinase cascades, three protein kinases are sequentially activated in response to appropriate extracellular stimuli and allow for signal amplification at each step of the cascade. The RAF-MEK-ERK MAP kinase cascade appears to be intimately involved in the regulation of cell cycle pro- gression and apoptosis. Indeed, activating mutations in B-Raf, one of the Raf family members, are reported to be present in 66% of malignant melanomas. 2 Disruption of this signaling cascade could thus offer a novel ap- proach for cancer chemotherapy. 3 Conversely, increased activation of ERK1/2 has been reported in a number of in vitro models of neuronal cell death and following focal cerebral ischemia in in vivo rodent models of stroke. 4 Furthermore, inhibition of the cascade at the MEK level has proved to be neuroprotective leading to a significant reduction in infarct volume in such animal models. 5 N H N N F N H N N Cl OH (1) B-Raf IC 50 900nM (2) B-Raf IC 50 10nM We sought to identify inhibitors of B-Raf, the likely ma- jor Raf isoform in the central nervous system, to assess their potential as neuroprotective agents in the treat- ment of stroke. Screening of the SmithKline Beecham compound bank identified the tri-substituted imidazole (1) as a sub- micromolar inhibitor of B-Raf. Concurrently we became aware of a poster publication from Merck disclosing a related tri-aryl imidazole 2 (L-779,450) as a highly potent low nanomolar inhibitor of Raf. 6 Compound (2) Bioorganic & Medicinal Chemistry Letters 16 (2006) 378–381 0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2005.09.072 Keywords: B-Raf; Imidazole. * Corresponding author. Tel.: +44 (0) 1279 627686; fax: +44 (0) 1279 622260; e-mail: Andy.K.Takle@gsk.com