913067-91-1Relevant articles and documents
Discovery of aminoquinazolines as potent, orally bioavailable inhibitors of Lck: Synthesis, SAR, and in vivo anti-inflammatory activity
DiMauro, Erin F.,Newcomb, John,Nunes, Joseph J.,Bemis, Jean E.,Boucher, Christina,Buchanan, John L.,Buckner, William H.,Cee, Victor J.,Chai, Lilly,Deak, Holly L.,Epstein, Linda F.,Faust, Ted,Gallant, Paul,Geuns-Meyer, Stephanie D.,Gore, Anu,Gu, Yan,Henkle, Brad,Hodous, Brian L.,Hsieh, Faye,Huang, Xin,Kim, Joseph L.,Lee, Josie H.,Martin, Matthew W.,Masse, Craig E.,McGowan, David C.,Metz, Daniela,Mohn, Deanna,Morgenstern, Kurt A.,Oliveira-Dos-Santos, Antonio,Patel, Vinod F.,Powers, David,Rose, Paul E.,Schneider, Stephen,Tomlinson, Susan A.,Tudor, Yan-Yan,Turci, Susan M.,Welcher, Andrew A.,White, Ryan D.,Zhao, Huilin,Zhu, Li,Zhu, Xiaotian
, p. 5671 - 5686 (2007/10/03)
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 (ED50 of 22 and 11 mg/kg, respectively) in the anti-CD3-induced production of interleukin-2 (IL-2) in mice.
