Hirabayashi Akihito, Mukaiyama Harunobu, Kobayashi Hiroaki, Shiohara Hiroaki, Nakayama Satoko, Ozawa Motoyasu, Miyazawa Keiji, Misawa Keiko, Ohnota Hideki, Isaji Masayuki
Central Research Laboratory, Kissei Pharmaceutical Company, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano Prefecture 399-8304, Japan.
Bioorg Med Chem. 2009 Jan 1;17(1):284-94. doi: 10.1016/j.bmc.2008.10.070. Epub 2008 Nov 5.
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.
70 kDa的ζ相关蛋白（ZAP-70）是一种脾酪氨酸激酶（Syk）家族激酶，通常在T细胞和自然杀伤细胞上表达，在T细胞免疫反应激活中起关键作用。因此，选择性ZAP-70抑制剂不仅可能对治疗自身免疫性疾病有用，而且对抑制器官移植排斥也有用。在我们最近关于Syk家族激酶抑制剂合成的研究中，我们发现新型咪唑并[1,2-c]嘧啶-8-甲酰胺衍生物具有强大的ZAP-70抑制活性，对ZAP-70的选择性优于其他激酶。特别是，化合物26对ZAP-70激酶表现出优异的抑制作用，并且对ZAP-70的选择性高于结构相关的Syk。一种强效、高选择性的ZAP-70抑制剂的发现将为自身免疫性疾病和器官移植药物治疗提供一种新的治疗工具。
