Hirabayashi Akihito, Mukaiyama Harunobu, Kobayashi Hiroaki, Shiohara Hiroaki, Nakayama Satoko, Ozawa Motoyasu, Tsuji Eiichi, Miyazawa Keiji, Misawa Keiko, Ohnota Hideki, Isaji Masayuki
Central Research Laboratory, Kissei Pharmaceutical Company Ltd, 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano-Pref 399-8304, Japan.
Bioorg Med Chem. 2008 Oct 15;16(20):9247-60. doi: 10.1016/j.bmc.2008.09.015. Epub 2008 Sep 9.
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.
脾酪氨酸激酶（Syk）和70kDa的ζ相关蛋白激酶（ZAP-70）是Syk家族成员和非受体型蛋白酪氨酸激酶，它们在B细胞和T细胞活化中起关键作用。因此，Syk家族酪氨酸激酶抑制剂将是治疗各种过敏性疾病和自身免疫性疾病的有用治疗剂。此前，我们报道1,2,4-三唑并[4,3-c]嘧啶衍生物1和1,2,4-三唑并[1,5-c]嘧啶衍生物2对Syk家族激酶表现出强烈的抑制活性。这些化合物在细胞试验中也表现出对IL-2的高水平抑制。然而，它们在IL-2产生的小鼠模型中的口服疗效较差。为了提高口服效果，我们研究了一系列新的Syk家族激酶抑制剂。我们发现咪唑并[1,2-c]嘧啶衍生物能有效抑制Syk家族激酶。在这些药物中，化合物9f不仅在体外对Syk和ZAP-70激酶表现出强烈的抑制活性，而且其口服给药导致小鼠模型中被动皮肤过敏反应和伴刀豆球蛋白A诱导的IL-2产生的体内抑制。
