Substituted isoquinolines and quinazolines as potential antiinflammatory agents.: Synthesis and biological evaluation of inhibitors of tumor necrosis factor α
Substituted isoquinolines and quinazolines as potential antiinflammatory agents.: Synthesis and biological evaluation of inhibitors of tumor necrosis factor α
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DOI：
10.1021/jm9805900
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发表时间：
1999-09-23
影响因子：
7.3
通讯作者：
Cottam, HB
中科院分区：
文献类型：
--
作者：
Chao, Q;Deng, L;Cottam, HB
制备了一系列异喹啉-1和喹唑啉-4及其衍生物，并对其在细菌脂多糖（LPS）刺激下抑制人外周血单核细胞肿瘤坏死因子α (TNF α)产生的能力进行了评价。为了优化TNF α抑制活性，我们制备了一系列的n -烷酸酯。还进行了一些亲电和亲核取代。四碳烷烃酸酯在异喹啉和喹唑啉系列中均具有最佳的活性。异喹啉环上的氟、溴、硝基、乙酰和氨基甲基等环取代基导致活性显著丧失。同样，喹唑啉环上的类似基团也降低了抑制活性。然而，6-和7-氨基喹唑啉衍生物75和76是有效的抑制剂，在TNF α体外实验中，每种衍生物的IC50值约为5 μ M。然后使用小鼠体内肺部炎症模型来评估在初步体外实验中确定的有希望的候选化合物。在该吸入模型中选择化合物75进行进一步研究，发现lps处理小鼠支气管肺泡灌洗液中TNF α水平比对照组降低约50%。因此，在临床相关的炎症和纤维化动物模型中，像75这样的化合物可以有效地抑制促炎细胞因子如TNF α，可能有潜力成为新的抗炎药。最后，制备了一种适合于光亲和放射性标记化合物的喹唑啉衍生物，以帮助鉴定这些TNF α抑制剂的假定细胞靶标。
A series of isoquinolin-1-ones and quinazolin-4-ones and related derivatives were prepared and evaluated for their ability to inhibit tumor necrosis factor alpha (TNF alpha) production in human peripheral blood monocytes stimulated with bacterial lipopolysaccharide (LPS). In an effort to optimize the TNF alpha inhibitory activity, a homologous series of N-alkanoic acid esters was prepared. Several electrophilic and nucleophilic substitutions were also carried out. Alkanoic acid esters of four carbons were found to be optimum for activity in both the isoquinoline and quinazoline series. Ring substituents such as fluoro, bromo, nitro, acetyl, and aminomethyl on the isoquinoline ring resulted in a significant loss of activity. Likewise, similar groups on the quinazoline ring also reduced inhibitory activity. However, the 6- and 7-aminoquinazoline derivatives, 75 and 76, were potent inhibitors, with IC50 values in the TNF alpha in vitro assay of approximately 5 mu M for each. An in vivo mouse model of pulmonary inflammation was then used to evaluate promising candidate compounds identified in the primary in vitro assay. Compound 75 was selected for further study in this inhalation model, and was found to reduce the level of TNF alpha in brochoalveolar lavage fluid of LPS-treated mice by about 50% that of control mice. Thus, compounds such as 75, which can effectively inhibit proinflammatory cytokines such as TNF alpha in clinically relevant animal models of inflammation and fibrosis, may have potential as new antiinflammatory agents. Finally, a quinazoline derivative suitable to serve as a photoaffinity radiolabeled compound was prepared to help identify the putative cellular target(s) for these TNF alpha inhibitors.