New α-substituted succinate-based hydroxamic acids as TNFα convertase inhibitors

被引:80
作者
Barlaam, B
Bird, TG
Lambert-van der Brempt, C
Campbell, D
Foster, SJ
Maciewicz, R
机构
[1] Zeneca Pharmaceut, Ctr Rech, F-51689 Reims 2, France
[2] AstraZeneca Pharmaceut, Macclesfield SK10 4TG, Cheshire, England
关键词
D O I
10.1021/jm990377j
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNF alpha to TNF alpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC50: 3.8 nM; blood IC50: 7 mu M) and BB1101 (TACE IC50: 0.2 nM; blood IC50: 2.3 mu M) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC50: 0.57 nM; blood IC50: 0.28 mu M).
引用
收藏
页码:4890 / 4908
页数:19
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