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Novel bishydroxamic acids as 5-lipoxygenase inhibitors. 1994

K A Ohemeng, and V N Nguyen, and C F Schwender, and M Singer, and M Steber, and J Ansell, and W Hageman
R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869.

Two series of novel bishydroxamic acids 2 and 3 (types A and B) were synthesized and tested for inhibition of 5-lipoxygenase from rat basophile leukemia (RBL) cells. Both series were potent inhibitors of the isolated enzyme but only the type B reverse hydroxamic acids possessed significant oral activity. The most potent compound, orally, was 3a, [IC50 = 270 nM; ED50 = 1.86 mg/kg], which compares favorably with the clinically useful 5-lipoxygenase inhibitor, zileuton. Unlike known hydroxamic acid inhibitors, the oral activity in this series appears to be associated with the second hydroxamic acid group. The corresponding monohydroxamic acids retained inhibitor potency, in vitro, with reduced oral activity in a mouse zymosan peritonitis model. Compound 4e [IC50 = 7 nM], a monohydroxamic acid derivative related to 3a, is among the most potent inhibitors of the isolated enzyme yet to be reported.

UI MeSH Term Description Entries
D009637 Masoprocol A potent lipoxygenase inhibitor that interferes with arachidonic acid metabolism. The compound also inhibits formyltetrahydrofolate synthetase, carboxylesterase, and cyclooxygenase to a lesser extent. It also serves as an antioxidant in fats and oils. Nordihydroguaiaretic Acid,(R*,S*)-4,4'-(2,3-Dimethylbutane-1,4-diyl)bispyrocatechol,Actinex,Dihydronorguaiaretic Acid,Nordihydroguaiaretic Acid, (R*,S*)-Isomer,meso-Nordihydroguaiaretic Acid,Acid, meso-Nordihydroguaiaretic,meso Nordihydroguaiaretic Acid
D010538 Peritonitis INFLAMMATION of the PERITONEUM lining the ABDOMINAL CAVITY as the result of infectious, autoimmune, or chemical processes. Primary peritonitis is due to infection of the PERITONEAL CAVITY via hematogenous or lymphatic spread and without intra-abdominal source. Secondary peritonitis arises from the ABDOMINAL CAVITY itself through RUPTURE or ABSCESS of intra-abdominal organs. Primary Peritonitis,Secondary Peritonitis,Peritonitis, Primary,Peritonitis, Secondary
D006877 Hydroxamic Acids A class of weak acids with the general formula R-CONHOH. Hydroxamic Acid,Acid, Hydroxamic,Acids, Hydroxamic
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D016859 Lipoxygenase Inhibitors Compounds that bind to and inhibit that enzymatic activity of LIPOXYGENASES. Included under this category are inhibitors that are specific for lipoxygenase subtypes and act to reduce the production of LEUKOTRIENES. 5-Lipoxygenase Inhibitor,Lipoxygenase Inhibitor,12-Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors,Arachidonate 12-Lipoxygenase Inhibitors,Arachidonate 15-Lipoxygenase Inhibitors,Arachidonate 5-Lipoxygenase Inhibitors,Inhibitors, Lipoxygenase,12 Lipoxygenase Inhibitors,12-Lipoxygenase Inhibitors, Arachidonate,15 Lipoxygenase Inhibitors,15-Lipoxygenase Inhibitors, Arachidonate,5 Lipoxygenase Inhibitor,5 Lipoxygenase Inhibitors,5-Lipoxygenase Inhibitors, Arachidonate,Arachidonate 12 Lipoxygenase Inhibitors,Arachidonate 15 Lipoxygenase Inhibitors,Arachidonate 5 Lipoxygenase Inhibitors,Inhibitor, 5-Lipoxygenase,Inhibitor, Lipoxygenase,Inhibitors, 12-Lipoxygenase,Inhibitors, 15-Lipoxygenase,Inhibitors, 5-Lipoxygenase,Inhibitors, Arachidonate 12-Lipoxygenase,Inhibitors, Arachidonate 15-Lipoxygenase,Inhibitors, Arachidonate 5-Lipoxygenase
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus

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