ABSTRACT
Class A-class C mechanism-based beta-lactamase inhibitors were designed on the basis of the intermediacy of an oxycarbenium species capable of cross-linking with amino acids residues in the active site. Penams 24 and 27 were very potent against AmpC in vitro. The MIC values of 24 in combination with piperacillin against class A and class C producing organisms showed improvement over clinically used tazobactam.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins , Cyclopropanes/chemical synthesis , Diazonium Compounds/chemistry , Enzyme Inhibitors/chemical synthesis , Rhodium , Serine/chemistry , Spiro Compounds/chemical synthesis , Sulbactam/chemistry , beta-Lactamase Inhibitors , beta-Lactams/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Catalysis , Crystallography, X-Ray , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/drug effects , Microbial Sensitivity Tests , Models, Molecular , Pseudomonas aeruginosa/drug effects , Serratia marcescens/drug effects , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Sulbactam/analogs & derivatives , beta-Lactamases/chemistry , beta-Lactams/chemistry , beta-Lactams/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.
Subject(s)
Hydroxamic Acids/chemical synthesis , Matrix Metalloproteinase Inhibitors , Osteoarthritis/drug therapy , Piperidines/chemical synthesis , Protease Inhibitors/chemical synthesis , Sulfones/chemical synthesis , ADAM Proteins , ADAM17 Protein , Administration, Oral , Animals , Binding Sites , Biological Assay , Cartilage/drug effects , Cartilage/enzymology , Cattle , Crystallography, X-Ray , Dialysis , Dogs , Haplorhini , Humans , Hydroxamic Acids/pharmacokinetics , Hydroxamic Acids/pharmacology , Male , Matrix Metalloproteinase 13 , Matrix Metalloproteinases/chemistry , Metalloendopeptidases/antagonists & inhibitors , Mice , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rabbits , Rats , Structure-Activity Relationship , Sulfones/pharmacokinetics , Sulfones/pharmacologyABSTRACT
Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamases, which destroy beta-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a beta-lactam antibiotic and a beta-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available beta-lactamase inhibitors against class C enzymes and new variants of beta-lactamases, there is a need to develop an inhibitor with broad-spectrum activity. Since the discovery of clavulanic acid, there has been an enormous research effort in this area to identify better antibiotic/inhibitor combinations and to understand the molecular bases for interactions between beta-lactam antibiotics, beta-lactamases, and beta-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new beta-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.
