Kottirsch Georg, Koch Guido, Feifel Roland, Neumann Ulf
Preclinical Research Novartis Pharma AG, CH-4002 Basel, Switzerland.
J Med Chem. 2002 May 23;45(11):2289-93. doi: 10.1021/jm0110993.
Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
通过克莱森-爱尔兰重排反应合成了新型的肿瘤坏死因子转化酶（TACE）和基质金属蛋白酶（MMPs）的异羟肟酸酯抑制剂。引入芳基残基以填充酶的P1'特异性口袋。最佳化合物对MMPs和TACE的抑制活性达纳摩尔级别，并且以48 nM的IC50抑制细胞中TNFα的释放。对大鼠口服给药可抑制脂多糖诱导的血浆TNFα水平，ED50为1 mg/kg。
