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Design, Synthesis, and Evaluation of 4,6-diaminonicotinamide Derivatives as Novel and Potent Immunomodulators Targeting JAK3

Design, Synthesis, and Evaluation of 4,6-diaminonicotinamide Derivatives as Novel and Potent Immunomodulators Targeting JAK3

Yutaka Nakajima, Naohiro Aoyama, Fumie Takahashi, Hiroshi Sasaki, Keiko Hatanaka, Ayako Moritomo, Masamichi Inami, Misato Ito, Koji Nakamura, Fumihiro Nakamori, Takayuki Inoue, Shohei Shirakami

Bioorg Med Chem. 2016 Oct 1;24(19):4711-4722.

PMID: 27544589

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
CS31043269	Tacrolimus Related Compound A			Price

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