title: Structure-activity relationship studies of imidazo[1,2-c]pyrimidine derivatives as potent and orally effective Syk family kinases inhibitors.
abstract: Spleen tyrosine kinase (Syk) and zeta-associated protein kinase of 70k Da (ZAP-70) are members of the Syk family and non-receptor-type protein tyrosine kinases, which play crucial roles in B- and T-cell activation. Therefore, a Syk family tyrosine kinases inhibitor would be a useful therapeutic agent for the treatment of various allergic disorders and autoimmune diseases. Previously, we reported that 1,2,4-triazolo[4,3-c]pyrimidine derivative 1 and 1,2,4-triazolo[1,5-c]pyrimidine derivative 2 showed strong inhibitory activities against Syk family kinases. These compounds also exhibited high-level suppression of IL-2 in cellular assays. However, their oral efficacies were poor in a mouse model of IL-2 production. To improve oral effectiveness, we investigated a new series of Syk family kinases inhibitors. We found that imidazo[1,2-c]pyrimidine derivatives potently inhibited the Syk family kinases. Among these agents, compound 9f not only showed strong inhibitory activities against Syk and ZAP-70 kinases in vitro, but its oral administration resulted in the in vivo suppression of both the passive cutaneous anaphylaxis reaction and Concanavalin A-induced IL-2 production in a mouse model.
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: Eiichi
authors.initials: E
authors.lastname: Tsuji
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: D000284:Administration, Oral; D000818:Animals; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase