Smith P W, Sollis S L, Howes P D, Cherry P C, Starkey I D, Cobley K N, Weston H, Scicinski J, Merritt A, Whittington A, Wyatt P, Taylor N, Green D, Bethell R, Madar S, Fenton R J, Morley P J, Pateman T, Beresford A
Department of Enzyme Medicinal Chemistry, Glaxo Wellcome Research and Development Limited, Stevenage, Herts, U.K.
J Med Chem. 1998 Mar 12;41(6):787-97. doi: 10.1021/jm970374b.
4-Amino- and 4-guanidino-4H-pyran-6-carboxamides 4 and 5 related to zanamivir (GG167) are a new class of inhibitors of influenza virus sialidases. Structure--activity studies reveal that, in general, secondary amides are weak inhibitors of both influenza A and B viral sialidases. However, tertiary amides, which contain one or more small alkyl groups, show much greater inhibitory activity, particularly against the influenza A virus enzyme. The sialidase inhibitory activities of these compounds correlate well with their in vitro antiviral efficacy, and several of the most potent analogues displayed useful antiviral activity in vivo when evaluated in a mouse model of influenza A virus infection. Carboxamides which were highly active sialidase inhibitors in vitro also showed good antiviral activity in the mouse efficacy model of influenza A infection when administered intranasally but displayed modest activity when delivered by the intraperitoneal route.
与扎那米韦（GG167）相关的4-氨基-4H-吡喃-6-羧酰胺4和4-胍基-4H-吡喃-6-羧酰胺5是一类新型的流感病毒唾液酸酶抑制剂。构效关系研究表明，一般来说，仲酰胺是甲型和乙型流感病毒唾液酸酶的弱抑制剂。然而，含有一个或多个小烷基的叔酰胺表现出更强的抑制活性，尤其是对甲型流感病毒酶。这些化合物的唾液酸酶抑制活性与其体外抗病毒效力密切相关，在甲型流感病毒感染的小鼠模型中进行评估时，几种最有效的类似物在体内显示出有效的抗病毒活性。在体外具有高活性唾液酸酶抑制作用的羧酰胺，经鼻内给药时在甲型流感感染的小鼠效力模型中也显示出良好的抗病毒活性，但经腹腔途径给药时活性适中。
