ABSTRACT
The discovery of terphenyl derivatives as highly selective COX-2 inhibitors resulted from our efforts to overcome poor pharmacokinetics demonstrated by the COX-2 selective diarylthiophene DuP 697 [2-bromo-4-(4'-sulfonylmethyl)phenyl-5-(4'-fluoro)phenylthiophe ne]. Detailed SAR related to the ortho-biphenyls and variants of the central ring are described herein.
Subject(s)
Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacokinetics , Isoenzymes/drug effects , Molecular Structure , Prostaglandin-Endoperoxide Synthases/drug effects , Structure-Activity Relationship , Thiophenes/pharmacokineticsABSTRACT
Structure-activity relationships were explored for some analogs of Brequinar having a linking atom between the 2-biphenyl substituent and the quinoline ring. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to the overall shape and lipophilicity of the 2-substituent.
Subject(s)
Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Biphenyl Compounds/chemistry , Carbon/chemistry , Lymphocyte Culture Test, Mixed , Structure-Activity RelationshipABSTRACT
The structure-activity relationships of some tetracyclic heterocycles related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction are related to ring system, heteroatom placement, and pendant ring substitution.
Subject(s)
Biphenyl Compounds/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacology , Oxidoreductases Acting on CH-CH Group Donors , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Lymphocyte Culture Test, Mixed , Oxidoreductases/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
A series of 2,5-diarylisothiazolones is reported that inhibit the IL-1 beta-induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, nonpeptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
Subject(s)
Cartilage/drug effects , Enzyme Inhibitors/pharmacology , Interleukin-1/metabolism , Thiazoles/pharmacology , Animals , Cartilage/metabolism , Cattle , Hydrolysis , Interleukin-1/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Organ Culture Techniques , Osteoarthritis/metabolism , Osteoarthritis/prevention & control , Spectrophotometry, Infrared , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
Vinylogous hydroxamic acids (3-(N-hydroxy-N-alkylamino)-2-propen-1-ones, VHA) were prepared as antiinflammatory agents. The synthesis, chemical properties, and in vitro biological activities of these relatively unexplored compounds are described. The VHAs were prepared by condensation of the appropriate N-substituted hydroxylamine with any of the three reagents: a 1,3-dicarbonyl compound (method A); a vinylogous amide (method B); or an alkynone (method C). The VHAs exist as one or more tautomers in solution with the relative proportions of each being dependent upon the structure of the VHA, solvent, and pH. VHAs undergo some of the typical reactions of hydroxamic acids as well as those of vinylogous amides. VHAs are active as inhibitors of 5-lipoxygenase and of IL-1 biosynthesis in vitro, which do not inhibit other enzymes of the arachidonic acid cascade. They have been shown by ESR studies to bring about inhibition of soybean type 1 15-lipoxygenase by reduction of the active site iron.
