ABSTRACT
A series of alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the alpha-amino group (P(1) position), as well as different groups attached to the sulphone group extending into P(1)'. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of >1000x for a number of analogues.
Subject(s)
Enzyme Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Collagenases/metabolism , Enzyme Inhibitors/chemistry , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 13 , Structure-Activity RelationshipABSTRACT
A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.
Subject(s)
Alkanes/pharmacology , Enzyme Inhibitors/pharmacology , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Alkanes/chemistry , Collagenases/metabolism , Enzyme Inhibitors/chemistry , Hydroxamic Acids/chemistry , Inhibitory Concentration 50 , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 13 , Matrix Metalloproteinase 2/metabolism , Structure-Activity RelationshipABSTRACT
This letter describes SAR exploration and rat PK optimization of a series of novel, MMP-1 sparing aryl hydroxamate sulfonamides with activity against MMP-2 and MMP-13.
Subject(s)
Matrix Metalloproteinase Inhibitors , Piperidines/chemistry , Piperidines/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Administration, Oral , Animals , Biological Availability , Drug Design , Matrix Metalloproteinase 13 , Rats , Structure-Activity RelationshipABSTRACT
A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Collagenases/chemistry , Collagenases/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/pharmacology , Humans , Hydroxamic Acids/chemical synthesis , Inhibitory Concentration 50 , Matrix Metalloproteinase 1/chemistry , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 13 , Matrix Metalloproteinase 2/chemistry , Matrix Metalloproteinase 2/metabolism , Models, Molecular , Structure-Activity RelationshipABSTRACT
We have discovered a new series of potent MMP Inhibitors that are selective for MMP-13 over MMP-1 incorporating a gamma-sulfone thiol.
Subject(s)
Extracellular Matrix/enzymology , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/pharmacology , Sulfhydryl Compounds/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Sulfhydryl Compounds/chemical synthesis , Sulfhydryl Compounds/chemistryABSTRACT
A sensitive RNAse protection method was used to show that serine protease inhibitor-1 (Spi-1) is expressed in rat liver and heart, but not in kidney or brain. Bovine somatotropin (bGH) and placental lactogen (bPL) induced rat hepatocyte cultures to express both Spi-1 and IGF-1 mRNA, with bPL approximately 100-fold more potent than bGH. Bovine prolactin (bPrL) did not induce hepatocyte Spi-1 mRNA, demonstrating lack of involvement of lactogenic receptors. Albumin mRNA levels were stable during hepatocyte culturing and were unaffected by growth hormone (GH) treatment, showing that neither culture conditions nor GH treatment affected cellular differentiation. Eliminating serum-free medium hormone supplements one at a time, estradiol, testosterone and T3 were shown to be unnecessary for GH induction of Spi-1, while dexamethasone removal decreased Spi-1 mRNA levels to 10% of GH-stimulated controls. bGH induction of Spi-1 mRNA in the presence of only dexamethasone and glucagon was 75% higher (p < 0.01) than levels seen with insulin also present.
