Venkatesan Aranapakam M, Davis Jamie M, Grosu George T, Baker Jannie, Zask Arie, Levin Jeremy I, Ellingboe John, Skotnicki Jerauld S, Dijoseph John F, Sung Amy, Jin Guixian, Xu Weixin, McCarthy Diane Joseph, Barone Dauphine
Wyeth Research, Pearl River, New York 10965, USA.
J Med Chem. 2004 Dec 2;47(25):6255-69. doi: 10.1021/jm040086x.
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
合成了一系列4-炔氧基苯基硫烷基、亚磺酰基和磺酰基烷基以及哌啶-4-羧酸异羟肟酸酯。通过研究硫的氧化态和改变P1'取代基，展示了它们对肿瘤坏死因子-α（TACE）和基质金属蛋白酶（MMP）抑制活性的构效关系。带有4-丁炔氧基部分的磺酰基衍生物20-24是比所测试的MMPs更具选择性的TACE抑制剂。亚磺酰基衍生物如化合物25-28对硫上的特定氧化表现出偏好。在磺酰基系列中也证明了对MMPs的选择性。在哌啶系列中引入丁炔氧基取代基后，细胞活性增强。化合物64和65在小鼠中以100mg/kg口服给药时是TNF-α释放的有效抑制剂。
