Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.

Article Details

Citation

Almstead NG, Bradley RS, Pikul S, De B, Natchus MG, Taiwo YO, Gu F, Williams LE, Hynd BA, Janusz MJ, Dunaway CM, Mieling GE

Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.

J Med Chem. 1999 Nov 4;42(22):4547-62.

PubMed ID
10579818 [ View in PubMed
]
Abstract

The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
N-Hydroxy-4-[(4-Methoxylphenyl)Sulfonyl]-2,2-Dimethyl-Hexahydro-1,4-Thiazepine-3(S)-CarboxamideStromelysin-1IC 50 (nM)0.7N/AN/ADetails