ABSTRACT
Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3-carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothizines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4-dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Isoenzymes/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Thiazines/pharmacology , Thiazoles/pharmacology , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/chemical synthesis , Humans , Magnetic Resonance Spectroscopy , Meloxicam , Membrane Proteins , Molecular Structure , Recombinant Proteins/metabolism , Structure-Activity Relationship , Substrate Specificity , Thiazines/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A variety of modern biotechnical approaches are available to assist in optimizing and controlling bioremediation processes. These approaches are broad-ranging, and may include genetic engineering to improve biodegradative performance, maintenance of the environment, and process monitoring and control. In addition to direct genetic engineering strategies, molecular diagnostic and monitoring technology using DNA gene probing methods and new quantitative mRNA analytical procedures allows direct analysis of degradative capacity, activity, and response under in situ conditions. Applications of these molecular approaches in process developments for trichloroethylene (TCE), polychlorinated biphenyls (PCB), and polynuclear aromatic hydrocarbons (PAH) bio-oxidation in soils, aquifer sediments, and ground-water treatment reactors have been demonstrated. Molecular genetic technologies permit not only the development of new processes for bioremediation, but also new process monitoring, control strategies, and molecular optimization paradigms that take full advantage of vast and diverse abilities of microorganisms to destroy problem chemicals.
