New α-Substituted Succinate-Based Hydroxamic Acids as TNFα Convertase Inhibitors

Abstract

Tumor necrosis factor α convertase (TACE), the enzyme responsible for the processing of pro-TNFα to TNFα, 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 μM) and BB1101 (TACE IC₅₀: 0.2 nM; blood IC₅₀: 2.3 μM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky α-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 μM).