ABSTRACT
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Subject(s)
ADAM Proteins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemical synthesis , Hydroxamic Acids/chemical synthesis , Sulfonamides/chemical synthesis , ADAM17 Protein , Animals , Biological Availability , Caspase Inhibitors , Cell Line , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/pharmacokinetics , Cysteine Proteinase Inhibitors/pharmacology , Dogs , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Inhibitory Concentration 50 , Lipopolysaccharides/pharmacology , Mice , Molecular Structure , Monocytes , Rats , Species Specificity , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/drug effectsABSTRACT
Several alkenyl derivatives were prepared using allyl penam sulfone as the key intermediate. Isomers of these derivatives having beta configuration at C-6 showed potent activity against CcrA enzyme. A new method was developed to prepare propargyl penam sulfone. The majority of the triazoles prepared by this route exhibited good activity against all three representative enzymes used for the inhibition assay.
Subject(s)
Bacterial Proteins , Enzyme Inhibitors/pharmacology , Sulfones/pharmacology , Triazoles/pharmacology , beta-Lactamase Inhibitors , Alkenes/chemical synthesis , Alkynes/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Escherichia coli , Inhibitory Concentration 50 , Molecular Conformation , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/pharmacology , Sulfones/chemical synthesis , Tazobactam , Triazoles/chemical synthesis , beta-LactamasesABSTRACT
6-(Nitrileoxidomethyl) penam sulfone intermediate was prepared in a few steps starting from commercially available (+)-6-aminopenicillanic acid. This intermediate underwent smooth 1, 3-dipolar cycloaddition reactions with various alkenes and alkynes to give cycloadducts in moderate to good yields. By this new method, several potent beta-lactamase inhibitors were synthesized. The regio- and stereoselectivity outcomes of the cycloaddition process are also discussed.
