Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
Bioorg Med Chem Lett. 2011 Jan 15;21(2):660-3. doi: 10.1016/j.bmcl.2010.12.013. Epub 2010 Dec 8.
Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.
对一系列 2,4-二氨基嘧啶的 SAR 进行研究，得到了一些 c-Met 抑制剂，其中激酶选择性通过连接在 C4-氨甲酰苯甲酰胺环和 C2-氨基芳基环上的取代基来调节。进一步对 C2-氨基芳基进行先导化合物优化，得到了苯并噁嗪类似物，其药物性质受苯并噁嗪氮上取代基的性质调节。在 GTL-16 肿瘤异种移植小鼠模型中评估一种口服生物利用的类似物时，观察到肿瘤停滞（伴有部分消退）。随后的 PK/PD 研究表明，一种代谢物对整体体内反应有贡献。
