Design, synthesis, and evaluation of 4,6-diaminonicotinamide derivatives as novel and potent immunomodulators targeting JAK3

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• 作者：Yutaka Nakajima ; ^{yutaka.nakajima@astellas.com" class="auth_mail" title="E-mail the corresponding author} ; Naohiro Aoyama ; Fumie Takahashi ; Hiroshi Sasaki ; Keiko Hatanaka ; Ayako Moritomo ; Masamichi Inami ; Misato Ito ; Koji Nakamura ; Fumihiro Nakamori ; Takayuki Inoue ; Shohei Shirakami ; ^{shohei.shirakami@astellas.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：JAK3 (Janus kinase 3) ; Immunomodulator ; Transplant rejection ; hERG (human ether-a-go-go related gene)
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：24
• 期：19
• 页码：4711-4722
• 全文大小：2656 K

文摘

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.