- Structure-activity relationship and pharmacokinetic studies of sotrastaurin (aeb071), a promising novel medicine for prevention of graft rejection and treatment of psoriasis
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Protein kinase C (PKC) isotypes have emerged as key targets for the blockade of early T-cell activation. Herein, we report on the structure-activity relationship and the detailed physicochemical and in vivo pharmacokinetic properties of sotrastaurin (AEB071, 1), a novel maleimide-based PKC inhibitor currently in phase II clinical trials. Most notably, the preferred uptake of sotrastaurin into lymphoid tissues is an important feature, which is likely to contribute to its in vivo efficacy.
- Wagner, Jürgen,Von Matt, Peter,Faller, Bernard,Cooke, Nigel G.,Albert, Rainer,Sedrani, Richard,Wiegand, Hansj?rg,Jean, Christian,Beerli, Christian,Weckbecker, Gisbert,Evenou, Jean-Pierre,Zenke, Gerhard,Cottens, Sylvain
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p. 6028 - 6039
(2011/10/09)
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- Discovery of 3-(1H-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4- yl]-pyrrole-2,5-dione (AEB071), a potent and selective inhibitor of protein kinase C isotypes
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A series of novel maleimide-based inhibitors of protein kinase C(PKC) were designed, synthesized, and evaluated. AEB071 (1) was found to be a potent, selective inhibitor of classical and novel PKC isotypes. 1 is a highly efficient immunomodulator, acting via inhibition of early T cell activation. The binding mode of maleimides to PKCs, proposed by molecular modeling, was confirmed by X-ray analysis of 1 bound in the active site of PKCα. 2009 American Chemical Society.
- Wagner, Jürgen,Von Matt, Peter,Sedrani, Richard,Albert, Rainer,Cooke, Nigel,Ehrhardt, Claus,Geiser, Martin,Rummel, Gabriele,Stark, Wilhelm,Strauss, Andre,Cowan-Jacob, Sandra W.,Beerli, Christian,Weckbecker, Gisbert,Evenou, Jean-Pierre,Zenke, Gerhard,Cottens, Sylvain
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supporting information; experimental part
p. 6193 - 6196
(2010/04/02)
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