Wentland M P, Carlson J A, Dorff P H, Aldous S C, Perni R B, Young D C, Woods M G, Kingsley S D, Ryan K A, Rosi D
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Sterling Winthrop Inc., Collegeville, Pennsylvania 19426-0900, USA.
J Med Chem. 1995 Jul 7;38(14):2541-5. doi: 10.1021/jm00014a006.
Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated. Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study. The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity. In vitro activity did not translate to in vivo efficacy. For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.
受3-喹啉甲酰胺的抗疱疹特性以及平面分子内氢键连接的β-酮酰胺药效团的重要性的支持，已对一系列新型构象刚性类似物进行了评估，这些类似物在喹啉环的3位和4位之间含有一个杂环桥。两种异恶唑稠合衍生物17和23表现出良好的体外抗疱疹效力，与用作本研究对照结构的3-喹啉甲酰胺1相似。吡唑、吡咯和嘧啶衍生物的活性明显较低或无活性。体外活性并未转化为体内疗效。对于17，体内活性缺乏可能是由于相对于对HSV-2的MIC，小鼠体内血浆药物水平（Cmax和持续时间）不足所致。
