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  2. Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity

Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity

  • Bioorg Med Chem. 2003 Dec 1;11(24):5461-84. doi: 10.1016/j.bmc.2003.09.015.
Morten Dahl Sørensen 1 Lars K A Blaehr Mette K Christensen Thomas Høyer Scilla Latini Pernille-Julia V Hjarnaa Fredrik Björkling
Affiliations

Affiliation

  • 1 Medicinal Chemistry Research, LEO Pharma, Industriparken 55, DK-2750 Ballerup, Denmark. morten.soerensen@leo-pharma.com
Abstract

The design, synthesis, and structure-activity relationship (SAR) of a series of novel nonpeptidic cyclic phosphon- and phosphinamide-based hydroxamic acids as inhibitors of Matrix Metalloproteinases MMP-1, MMP-3, and MMP-9 are presented. Based on modelling studies and X-ray analysis, a model of the binding mode of these novel compounds in the MMP active site was obtained. This model provided a rational explanation for the observed SAR data, which included a systematic study of different S1' directed substituents, zinc-complexing groups, chirality, and variation of the cyclic phosphon- and phosphinamide rings. The in vivo effect of four compounds in a human fibrosarcoma mouse model (HT1080) was evaluated and compared to that of a reference compound, Prinomastat. Inhibition of tumour growth was observed for all four compounds.

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