Protein kinase C theta (PKC?) is a serine/threonine kinase predominantly expressed on T lymphocytes and the skeletal muscle. Pharmacological studies revealed that PKC? plays an important role in T cell signaling leading to the production of IL-2 and T cell activation, and it is also well validated by the extensive studies with knockout mice. Therefore, PKC? inhibitors offer significant potential as new treatments for transplant rejection and autoimmune diseases.As part of our research program directed at the development of new PKC? inhibitors, we have investigated a novel series of 2,4-diaminopyrimidine derivatives bearing a cross-linked cyclic moiety in the side chain. From this series, AS2521780 was identified as a potent and selective PKC? inhibitor which was efficacious both in rat heterotopic cardiac transplant and monkey renal transplant models. The synthesis and SAR of this novel series of PKC? inhibitors will be discussed. In addition, pharmacological profile of AS2521780 will be presented.

Discovery of AS2521780, a novel, potent, selective PKC[theta] inhibitor as an immunosuppressive agent

245th National Meeting (2013)

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