New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.

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Barlaam B, Bird TG, Lambert-Van Der Brempt C, Campbell D, Foster SJ, Maciewicz R

New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.

J Med Chem. 1999 Nov 18;42(23):4890-908.

PubMed ID

10579851 [ View in PubMed

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Abstract

Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, 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 IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) 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 IC(50): 0.57 nM; blood IC(50): 0.28 microM).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Marimastat	Interstitial collagenase	IC 50 (nM)	5	N/A	N/A	Details
Marimastat	Neutrophil collagenase	IC 50 (nM)	2	N/A	N/A	Details