title: 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.
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.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1 Kashiwabara, Hotaka, Azumino-City, Nagano-Pref 399-8304, Japan. akihito_hirabayashi@pharm.kissei.co.jp
authors.forename: Akihito
authors.initials: A
authors.lastname: Hirabayashi
authors.forename: Harunobu
authors.initials: H
authors.lastname: Mukaiyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shiohara
authors.forename: Satoko
authors.initials: S
authors.lastname: Nakayama
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Ozawa
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Misawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohnota
authors.forename: Masayuki
authors.initials: M
authors.lastname: Isaji
mesh_terms: 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
chemical_list: D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase