Sulfone reverse hydroxamates as matrix metalloproteinase inhibitors

Abstract

Abbott has disclosed matrix metalloproteinase inhibitors (MMPIs) characterised by N-formyl-N-hydroxyamino as the zinc ligand, (4-substituted)phenylsulfonyl as the P1' group fitting the primary specificity pocket of the enzymes and three different spacers (-C-C-C-, -C-C-NR-, -C-C-) connecting these structural elements. As such, the Abbott compounds can be regarded as reverse hydroxamate analogues of the well known classes of ?-sulfone, sulfonamide and β-sulfone hydroxamate MMPIs. Within the β-sulfones, a five-membered saturated heterocyclic ring appended at C-1, especially 1,3-dioxolane, identifies a structural subset claimed as having a unique combination of potency, pharmacokinetics and fewer side effects. A specific compound is singled out, (1S)-1-[(4S)- 2,2-dimethyl-1,3-dioxolan-4-yl]-2-[[4-[4-(trifluoromethoxy)phenoxy]- phenyl]sulfonyl] ethyl(N-hydroxy)formamide. Potent inhibition of MMP-2 (gelatinase A) is documented, especially among the β-sulfones. These compounds are stated to have utility for the treatment of diseases involving tissue degenerative processes, including rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, gingivitis, corneal, epidermal or gastric ulceration and tumour growth and metastasis.

• arthritis
• cancer
• gelatinase
• MMP
• MMP-2
• MMPI
• reverse hydroxamate