ABSTRACT
Conformationally constrained tetracyclic fluoroquinolones (FQs) were synthesized and profiled for their microbiological spectrum. The installation of a seven-membered ring between the pyrrolidine substituents and the C8 position on the FQ core scaffold resulted in a remarkable enhancement of microbiological potency toward both Gram-positive and Gram-negative bacteria. Focused optimization of seven-membered ring composition, stereochemistry, and amine placement led to the discovery of the two lead compounds that were selected for further progression.
Subject(s)
Fluoroquinolones/chemical synthesis , Fluoroquinolones/pharmacology , Tetracyclines/chemical synthesis , Tetracyclines/pharmacology , Acinetobacter baumannii/drug effects , Microbial Sensitivity Tests , Molecular Structure , Pseudomonas aeruginosa/drug effects , Structure-Activity RelationshipABSTRACT
Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Cyclic S-Oxides/chemical synthesis , Oxazolidinones/chemical synthesis , Acetamides/pharmacology , Administration, Oral , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/toxicity , Biological Availability , Cyclic S-Oxides/pharmacology , Cyclic S-Oxides/toxicity , Dogs , Drug Resistance, Bacterial , Female , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Injections, Intravenous , Linezolid , Male , Mice , Microbial Sensitivity Tests , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase Inhibitors/toxicity , Oxazolidinones/pharmacology , Oxazolidinones/toxicity , Rats , Rats, Sprague-Dawley , Staphylococcal Infections/drug therapy , Staphylococcus aureus , Streptococcal Infections/drug therapy , Streptococcus pyogenes , Structure-Activity RelationshipABSTRACT
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.
Subject(s)
Drug Design , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Cell Line , Cricetinae , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Liver/drug effects , Liver/enzymology , Molecular Structure , Muscle Cells/drug effects , Muscle Cells/enzymology , Pyrazoles/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.
