新型吡啶并[2,3-d]嘧啶酪氨酸激酶抑制剂系列的构效关系

Structure-activity relationships for a novel series of pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors.

作者信息

Hamby J M, Connolly C J, Schroeder M C, Winters R T, Showalter H D, Panek R L, Major T C, Olsewski B, Ryan M J, Dahring T, Lu G H, Keiser J, Amar A, Shen C, Kraker A J, Slintak V, Nelson J M, Fry D W, Bradford L, Hallak H, Doherty A M

机构信息

Parke-Davis Pharmaceutical Research, Division of Warner Lambert Company, Ann Arbor, Michigan 48105, USA.

出版信息

J Med Chem. 1997 Jul 18;40(15):2296-303. doi: 10.1021/jm970367n.

DOI:10.1021/jm970367n

Abstract

Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- tert-butylurea (4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound 4b inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50 values of 1.11, 0.13, 0.45, and 0.22 microM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2-position of 4b afforded compound 6c with enhanced potency and bioavailability. Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC50 of 0.3 microM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with a 6-(3',5'-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor 4e. Compound 4e inhibited the FGFr tyrosine kinase with an IC50 of 0.060 microM, whereas IC50s for the inhibition of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 microM.

摘要

对一个化合物库进行筛选以寻找成纤维细胞生长因子（FGFr）和血小板衍生生长因子（PDGFr）受体酪氨酸激酶的抑制剂，从而开发出了一系列新型的ATP竞争性吡啶并[2,3 - d]嘧啶酪氨酸激酶抑制剂。最初的先导化合物1 - [2 - 氨基 - 6 - （2,6 - 二氯苯基）吡啶并[2,3 - d]嘧啶 - 7 - 基] - 3 - 叔丁基脲（4b，PD - 089828）被发现是一种具有广泛活性的酪氨酸激酶抑制剂。化合物4b抑制PDGFr、FGFr、EGFr和c - src酪氨酸激酶，其IC50值分别为1.11、0.13、0.45和0.22微摩尔。随后的构效关系研究导致合成了相对于最初先导化合物具有更高活性、溶解性和生物利用度的新类似物。例如，在4b的2 - 位引入[4 - （二乙氨基）丁基]氨基侧链得到了活性和生物利用度增强的化合物6c。化合物6c抑制血小板衍生生长因子刺激的血管平滑肌细胞增殖，IC50为0.3微摩尔。此外，用6 - （3',5' - 二甲氧基苯基）官能团取代4b的6 - （2,6 - 二氯苯基）部分产生了一种高度选择性的FGFr酪氨酸激酶抑制剂4e。化合物4e抑制FGFr酪氨酸激酶的IC50为0.060微摩尔，而该化合物（4e）抑制PDGFr、FGFr、EGFr、c - src和InsR酪氨酸激酶的IC50均大于50微摩尔。