AEB071:Oral and Specific Inhibitor of T Cell Activation for the Prevention of Graft Rejection and th

• 作 者: JürgenWagner;
• 机 构: Novartis Institutes for Biomedical Research Switzerland
• 出 处: 中国上海第七届国际新药发明科技年会
• 发表日期: 2009年期

　　Inhibition ofT-cell activation is the most efficient way to prevent transplant rejection.Among the immunosuppressants currently on the market,only calcineurin inhibitors (CNIs) inhibit specifically T-cell activation,but their long term use is associated with side-effects (nephrotoxicity and cardiovascular side-effects).AEB071 is the first LMW inhibitor preventing T-cell activation via a calcineurin-independent pathway.AEB071 inhibits all classical and novel protein kinase C isotypes.Herein,we present the case story of AEB071 including the medicinal chemistry approaches,critical PK properties of the compound,preclinical data including in vivo models in rodents and non-human primates as well as positive proof-of-concept results obtained with AEB071 in psoriasis patients.Finally,we will also discuss the need of inhibition of multiple PKC isotypes versus specific inhibition of individual PKCs,namely PKC,to effectively suppress alloimmune responses.