Antiviral properties of 3-quinolinecarboxamides: a series of novel non-nucleoside antiherpetic agents.

Drug design and discovery Pub Date : 1997-05-01
M P Wentland, R B Perni, P H Dorff, R P Brundage, M J Castaldi, J A Carlson, T R Bailey, S C Aldous, P M Carabateas, E R Bacon, R K Kullnig, D C Young, M G Woods, S D Kingsley, K A Ryan, D Rosi, M L Drozd, F J Dutko
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引用次数: 0

Abstract

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.

3-喹啉羧基酰胺的抗病毒特性:一系列新的非核苷类抗疱疹药物。
新型抗疱疹药3-喹啉羧基酰胺作为斯特林温斯洛普公司药物发现项目的一部分被发现。本研究的一个主要目标是鉴定具有抗无环鸟苷抗性单纯疱疹病毒活性的新型非核苷类药物。在HSV-2斑块减少试验中筛选化合物文库,1-乙基-1,4-二氢-4-氧-7-(4-吡啶基)-3-喹啉甲酰胺(1)成为一个有吸引力的先导结构。通过对喹啉环的1-、2-、3-、4-和7位进行修饰,鉴定出了与阿昔洛韦相比体外效力提高了5倍的类似物。在单剂量小鼠感染模型中,1-(4-FC6H4)类似物17是体外最有效的衍生物之一,其口服抗疱疹效果与阿昔洛韦的1/16剂量相当;然而,在多次给药方案中,它的效力降低了2倍。作用机制研究表明,这些新化合物与阿昔洛韦不同的,尚未定义的分子靶标相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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