4ALV

The Design, Synthesis, and Biological Evaluation of Pim Kinase Inhibitors.

Tsuhako, A.L., Brown, D.S., Koltun, E.S., Aay, N., Arcalas, A., Chan, V., Du, H., Engst, S., Franzini, M., Galan, A., Huang, P., Johnston, S., Kane, B., Kim, M.H., Laird, A.D., Lin, R., Mock, L., Ngan, I., Pack, M., Stott, G., Stout, T.J., Yu, P., Zaharia, C., Zhang, W., Zhou, P., Nuss, J.M., Kearney, P.C., Xu, W.

(2012) Bioorg Med Chem Lett 22: 3732

• PubMed: 22542012 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2012.04.025
• Primary Citation of Related Structures:  
  4ALU, 4ALV, 4ALW


• PubMed Abstract: 
  

  A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.

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Organizational Affiliation: 

Exelixis, Department of Drug Discovery, South San Francisco, CA 94080, USA. alew@exelixis.com