Cyclic phosphinamides and phosphonamides, novel series of potent matrix metalloproteinase inhibitors with antitumour activity.
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.
Sørensen
Morten Dahl
MD
Medicinal Chemistry Research, LEO Pharma, Industriparken 55, DK-2750 Ballerup, Denmark. morten.soerensen@leo-pharma.com
Blaehr
Lars K A
LK
Christensen
Mette K
MK
Høyer
Thomas
T
Latini
Scilla
S
Hjarnaa
Pernille-Julia V
PJ
Björkling
Fredrik
F
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002455:Cell Division / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000577:Amides; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D063065:Organophosphonates; D011480:Protease Inhibitors