Boschelli D H, Wu Z, Klutchko S R, Showalter H D, Hamby J M, Lu G H, Major T C, Dahring T K, Batley B, Panek R L, Keiser J, Hartl B G, Kraker A J, Klohs W D, Roberts B J, Patmore S, Elliott W L, Steinkampf R, Bradford L A, Hallak H, Doherty A M
Departments of Medicinal Chemistry, Cancer Research, Vascular, Cardiac Diseases, Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
J Med Chem. 1998 Oct 22;41(22):4365-77. doi: 10.1021/jm980398y.
Screening of a compound library led to the identification of 2-amino-6-(2,6-dichlorophenyl)-8-methylpyrido[2,3-d]pyrimidine (1) as a inhibitor of the platelet-derived growth factor receptor (PDGFr), fibroblast growth factor receptor (FGFr), and c-src tyrosine kinases (TKs). Replacement of the primary amino group at C-2 of 1 with a 4-(N,N-diethylaminoethoxy)phenylamino group yielded 2a, which had greatly increased activity against all three TKs. In the present work, variation of the aromatic group at C-6 and of the alkyl group at N-8 of the pyrido[2,3-d]pyrimidine core provided several analogues that retained potency, including derivatives that were biased toward inhibition of the TK activity of PDGFr. Analogues of 2a with a 3-thiophene or an unsubstituted phenyl group at C-6 were the most potent inhibitors. Compound 54, which had IC50 values of 31, 88, and 31 nM against PDGFr, FGFr, and c-src TK activity, respectively, was active in a variety of PDGF-dependent cellular assays and blocked the in vivo growth of three PDGF-dependent tumor lines.
对一个化合物文库进行筛选后，鉴定出2-氨基-6-(2,6-二氯苯基)-8-甲基吡啶并[2,3-d]嘧啶(1)是血小板衍生生长因子受体(PDGFr)、成纤维细胞生长因子受体(FGFr)和c-src酪氨酸激酶(TKs)的抑制剂。用4-(N,N-二乙氨基乙氧基)苯基氨基取代1中C-2位的伯氨基得到2a，其对所有三种酪氨酸激酶的活性大大增强。在本研究中，吡啶并[2,3-d]嘧啶核心C-6位的芳基和N-8位的烷基的变化提供了几种保持效力的类似物，包括倾向于抑制PDGFr酪氨酸激酶活性的衍生物。在C-6位带有3-噻吩基或未取代苯基的2a类似物是最有效的抑制剂。化合物54对PDGFr、FGFr和c-src酪氨酸激酶活性的IC50值分别为31、88和31 nM，在多种PDGF依赖性细胞试验中具有活性，并阻断了三种PDGF依赖性肿瘤细胞系的体内生长。
