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.
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.
Hirabayashi
Akihito
A
Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1 Kashiwabara, Hotaka, Azumino-City, Nagano-Pref 399-8304, Japan. akihito_hirabayashi@pharm.kissei.co.jp
Mukaiyama
Harunobu
H
Kobayashi
Hiroaki
H
Shiohara
Hiroaki
H
Nakayama
Satoko
S
Ozawa
Motoyasu
M
Miyazawa
Keiji
K
Misawa
Keiko
K
Ohnota
Hideki
H
Isaji
Masayuki
M
D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000072377:Syk Kinase
D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase