A novel Syk family kinase inhibitor: design, synthesis, and structure-activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives.

Article Details

Citation

Copy to clipboard

Hirabayashi A, Mukaiyama H, Kobayashi H, Shiohara H, Nakayama S, Ozawa M, Miyazawa K, Misawa K, Ohnota H, Isaji M

A novel Syk family kinase inhibitor: design, synthesis, and structure-activity relationship of 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives.

Bioorg Med Chem. 2008 Aug 1;16(15):7347-57. doi: 10.1016/j.bmc.2008.06.017. Epub 2008 Jun 14.

PubMed ID

18585046 [ View in PubMed

]

Abstract

Splenic tyrosine kinase (Syk) family kinases, which are members of the protein tyrosine kinase family, play crucial roles in immune responses, with Syk participating in B-cell activation and the zeta-associated protein 70 kDa (ZAP-70) kinase being involved in T-cell activation. Therefore, Syk family kinase inhibitors are candidate therapeutic agents for the treatment of various allergic disorders and autoimmune diseases. We designed 1,2,4-triazolo[4,3-c]pyrimidine and 1,2,4-triazolo[1,5-c]pyrimidine derivatives as Syk family kinase inhibitors, based on literature reports and structure-based drug design. These derivatives showed significant Syk inhibitory activities, with ZAP-70 inhibition. Representative compounds 10d and 11 not only exhibited strong inhibition of both Syk and ZAP-70 kinase but also suppressed IL-2 production by peripheral blood mononuclear cells and whole blood.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Staurosporine	Tyrosine-protein kinase Lck	IC 50 (nM)	18	N/A	N/A	Details
Staurosporine	Tyrosine-protein kinase ZAP-70	IC 50 (nM)	53	N/A	N/A	Details