title: Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.
abstract: Zeta-associated protein, 70 kDa (ZAP-70), a spleen tyrosine kinase (Syk) family kinase, is normally expressed on T cells and natural killer cells and plays a crucial role in activation of the T cell immunoresponse. Thus, selective ZAP-70 inhibitors might be useful not only for treating autoimmune diseases, but also for suppressing organ transplant rejection. In our recent study on the synthesis of Syk family kinase inhibitors, we discovered that novel imidazo[1,2-c]pyrimidine-8-carboxamide derivatives possessed potent ZAP-70 inhibitory activity with good selectivity for ZAP-70 over other kinases. In particular, compound 26 showed excellent ZAP-70 kinase inhibition and high selectivity for ZAP-70 over structurally related Syk. The discovery of a potent, highly selective ZAP-70 inhibitor would contribute a new therapeutic tool for autoimmune diseases and organ transplant medication.
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 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: D000577:Amides; D001555:Benzene Derivatives; D006801:Humans; D007109:Immunity; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000577:Amides; D001555:Benzene Derivatives; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051746:ZAP-70 Protein-Tyrosine Kinase