Petrov Kimberly G, Zhang Yue-Mei, Carter Malcolm, Cockerill G Stuart, Dickerson Scott, Gauthier Cassandra A, Guo Yu, Mook Robert A, Rusnak David W, Walker Ann L, Wood Edgar R, Lackey Karen E
GlaxoSmithKline, Research Triangle Park, NC, USA.
Bioorg Med Chem Lett. 2006 Sep 1;16(17):4686-91. doi: 10.1016/j.bmcl.2006.05.090. Epub 2006 Jun 13.
Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
对6-呋喃基喹唑啉骨架进行合成修饰以优化对ErbB-1/ErbB-2双重酪氨酸激酶的抑制作用，得到了一致的构效关系，其中4-(3-氟苄氧基)-3-卤代苯胺具有最佳的酶活性和细胞选择性。对6-呋喃基的改变对酶活性影响较小，但似乎对细胞疗效有显著影响。拉帕替尼就是从这项研究中发现的。
