Ishida Hiroshi, Isami Shoichi, Matsumura Tsutomu, Umehara Hiroshi, Yamashita Yoshinori, Kajita Jiro, Fuse Eiichi, Kiyoi Hitoshi, Naoe Tomoki, Akinaga Shiro, Shiotsu Yukimasa, Arai Hitoshi
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan.
Bioorg Med Chem Lett. 2008 Oct 15;18(20):5472-7. doi: 10.1016/j.bmcl.2008.09.031. Epub 2008 Sep 11.
5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.
5-(1,3,4-恶二唑-2-基)嘧啶衍生物1是从我们的化合物库中鉴定出的一类新型FLT3抑制剂。为了通过对1进行微小修饰来增强所制备的2的抗肿瘤活性，对2嘧啶环2-、4-和5-位的侧链进行结构优化以提高代谢稳定性。在1,3,4-恶二唑基上引入极性取代基有助于显著提高代谢稳定性。结果，一系列化合物经口服给药后对小鼠MOLM-13异种移植模型显示出增强的疗效。
