ABSTRACT
Over 195 4-alkyl and 4,4-dialkyl 1,2-bis(4-chlorophenyl)pyrazolidine-3,5-dione derivatives were synthesized, utilizing microwave accelerated synthesis, for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good activity against MurB in vitro and low MIC values against gram-positive bacteria, particularly penicillin-resistant Streptococcus pneumoniae (PRSP). Derivative 7l demonstrated antibacterial activity against both gram-positive and gram-negative bacteria. Derivatives 7f and 10a also demonstrated potent nanomolar Kd values in their binding to MurB.
Subject(s)
Cell Wall/drug effects , Gram-Positive Bacteria/drug effects , Pyrazoles/pharmacology , Cell Wall/metabolism , Gram-Positive Bacteria/metabolism , Molecular StructureABSTRACT
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Metalloendopeptidases/antagonists & inhibitors , Sulfides/chemical synthesis , Sulfones/chemical synthesis , Sulfoxides/chemical synthesis , ADAM Proteins , ADAM17 Protein , Animals , Crystallography, X-Ray , Humans , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , In Vitro Techniques , Mice , Models, Molecular , Molecular Structure , Monocytes/drug effects , Monocytes/metabolism , Oxidation-Reduction , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Structure-Activity Relationship , Sulfides/chemistry , Sulfides/pharmacology , Sulfones/chemistry , Sulfones/pharmacology , Sulfoxides/chemistry , Sulfoxides/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Biological Assay , Cartilage/drug effects , Cartilage/enzymology , Cattle , Dialysis , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase 13 , Metalloendopeptidases/antagonists & inhibitors , Mice , Osteoarthritis/drug therapy , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
