2OG8

Discovery of Aminoquinazolines as Potent, Orally Bioavailable Inhibitors of Lck: Synthesis, SAR, and in Vivo Anti-Inflammatory Activity

DiMauro, E.F., Newcomb, J., Nunes, J.J., Bemis, J.E., Boucher, C., Buchanan, J.L., Buckner, W.H., Cee, V.J., Chai, L., Deak, H.L., Epstein, L.F., Faust, T., Gallant, P., Geuns-Meyer, S.D., Gore, A., Gu, Y., Henkle, B., Hodous, B.L., Hsieh, F., Huang, X., Kim, J.L., Lee, J.H., Martin, M.W., Masse, C.E., McGowan, D.C., Metz, D., Morgenstern, K.A., Oliveira-dos-Santos, A., Patel, V.F., Powers, D., Rose, P.E., Schneider, S., Tomlinson, S.A., Tudor, Y.Y., Turci, S.M., Welcher, A.A., White, R.D., Zhao, H., Zhu, L., Zhu, X.

(2006) J Med Chem 49: 5671-5686

• PubMed: 16970394 Search on PubMed
• DOI: https://doi.org/10.1021/jm0605482
• Primary Citation of Related Structures:  
  2OFV, 2OG8


• PubMed Abstract: 
  

  The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disease. Screening of our kinase-preferred collection identified aminoquinazoline 1 as a potent, nonselective inhibitor of Lck and T cell proliferation. In this report, we describe the synthesis and structure-activity relationships of a series of novel aminoquinazolines possessing in vitro mechanism-based potency. Optimized, orally bioavailable compounds 32 and 47 exhibit anti-inflammatory activity (ED(50) of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.

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Organizational Affiliation: 

Department of Medicinal Chemistry, Amgen, Inc., Cambridge, Massachusetts 02139, USA. edimauro@amgen.com