Design,synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3 |
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| Institution: | 1. GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK;2. AstraZeneca, Hodgkin Building, Chesterford Research Campus, Little Chesterford, Saffron Walden, Cambs. CB10 1XL, UK;1. University Medical Center Hamburg-Eppendorf, Department of Hepatobiliary and Transplant Surgery, Martinistraße 52, 20246 Hamburg, Germany;2. University Medical Center Hamburg-Eppendorf, Institute for Transfusion Medicine, Martinistraße 52, 20246 Hamburg, Germany;3. University Medical Center Hamburg-Eppendorf, Department of Medicine, Martinistraße 52, 20246 Hamburg, Germany |
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| Abstract: | In organ transplantation, T cell-mediated immune responses play a key role in the rejection of allografts. Janus kinase 3 (JAK3) is specifically expressed in hematopoietic cells and associated with regulation of T cell development via interleukin-2 signaling pathway. Here, we designed novel 4,6-diaminonicotinamide derivatives as immunomodulators targeting JAK3 for prevention of transplant rejection. Our optimization of C4- and C6-substituents and docking calculations to JAK3 protein confirmed that the 4,6-diaminonicotinamide scaffold resulted in potent inhibition of JAK3. We also investigated avoidance of human ether-a-go-go related gene (hERG) inhibitory activity. Selected compound 28 in combination with tacrolimus prevented allograft rejection in a rat heterotopic cardiac transplantation model. |
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| Keywords: | JAK3 (Janus kinase 3) Immunomodulator Transplant rejection hERG (human ether-a-go-go related gene) |
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