Structure-activity relationship studies of 5-benzylaminoimidazo[1,2-c]pyrimidine-8-carboxamide derivatives as potent, highly selective ZAP-70 kinase inhibitors.
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.
Hirabayashi
Akihito
A
Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 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
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
D000577:Amides; D001555:Benzene Derivatives; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051746:ZAP-70 Protein-Tyrosine Kinase