TYROSINE KINASE INHIBITORS .5. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR 4-[(PHENYLMETHYL)AMINO]-QUINAZOLINES AND 4-(PHENYLAMINO)QUINAZOLINES AS POTENT ADENOSINE 5'-TRIPHOSPHATE BINDING-SITE INHIBITORS OF THE TYROSINE KINASE DOMAIN OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR
TYROSINE KINASE INHIBITORS .5. SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR 4-[(PHENYLMETHYL)AMINO]-QUINAZOLINES AND 4-(PHENYLAMINO)QUINAZOLINES AS POTENT ADENOSINE 5'-TRIPHOSPHATE BINDING-SITE INHIBITORS OF THE TYROSINE KINASE DOMAIN OF THE EPIDERMAL GROWTH-FACTOR RECEPTOR
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DOI：
10.1021/jm00018a008
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发表时间：
1995-09-01
影响因子：
7.3
通讯作者：
FRY, DW
中科院分区：
文献类型：
--
作者：
REWCASTLE, GW;DENNY, WA;FRY, DW
合成了一系列4-取代的喹唑啉及其相关化合物，并评价了它们对磷脂酶C-γ1衍生底物上的表皮生长因子受体酪氨酸激酶活性的抑制作用。结果表明，碱性环系具有较窄的构效关系，喹唑啉是首选发色团，苯胺基和苯胺基是首选侧链。在4-苯胺基系列中，苯环3位上的小亲油吸电子基团为类似物提供了增强的效力。研究了两个系列的化合物[4-(苯甲基)氨基]和4-(3-溴苯基)氨基]来测定喹唑啉取代基的相对分子质量。在活性较高的4-(3-溴苯基)氨基系列中，6位或7位的供电子基团(NH2，OMe)活性增加，这与喹唑啉环8位附近的高电子密度要求一致。6，7-二甲氧基衍生物是这两个系列中最有效的，4-(3-溴苯基)氨基衍生物(3)的IC50值为0.029 nM，使其成为迄今为止报道的对表皮生长因子受体酶酪氨酸激酶活性最有效的抑制剂。
A series of 4-substituted quinazolines and related compounds have been prepared and evaluated for their ability to inhibit the tyrosine kinase activity of the epidermal growth factor receptor on a phospholipase C-gamma 1-derived substrate. The results show a narrow structure-activity relationship (SAR) for the basic ring system, with quinazoline being the preferred chromophore and benzylamino and anilino the preferred side chains. In the 4-anilino series, substitution on the 3-position of the phenyl ring with small lipophilic electron-withdrawing groups provided analogues with enhanced potency. Two series of compounds [4-(phenylmethyl)amino and 4-(3-bromophenyl)amino] were studied to determine SARs for quinazoline substituents. In the more active 4-(3-bromophenyl)amino series, electron-donating groups (NH2, OMe) at the 6- or 7-position increased activity, in a pattern consistent with a requirement for high electron density in the vicinity of the 8-position of the quinazoline ring. The 6,7-dimethoxy derivatives were the most effective in both series, with the 4-(3-bromophenyl)amino derivative (3) having an IC50 Of 0.029 nM, making it by far the most potent reported inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor enzyme.