Ronald L. Magolda

Novel Synthesis of Potent Site-Specific Phospholipase A2 Inhibitors

Phospholipase A2 (PLA2) is an esterase responsible for the liberation of phospholipid-bound arachidonic acid, a biosynthetic precursor of putative inflammatory mediators. Arachidonic acid is metabolized by cyclooxygenase and lipoxygenase to the corresponding prostaglandins and leukotrienes (Fig. 1). Traditional antiinflammatory therapy has relied on cyclooxygenase and more recently on lipoxygenase blockade (Shen, 1981), but direct control of arachidonic acid pools has remained relatively unexplored. Recent evidence (Hirata et al., 1980; Blackwell et al., 1980; Rothhut et al., 1983) demonstrates that antiinflammatory steroids control polyunsaturated fatty acid release at both cyclooxygense and lipoxygenase pathways by enhancing the production of PLA2 inhibitory proteins (lipomodulin, macrocortin, renocortin). Direct phospholipase A2 site-specific inhibition, therefore, offers new opportunities in antiinflammatory treatment.

Metabolism resistant isothiazolone inhibitors of cartilage breakdown

A series of 2-(arylmethyl)pyridoisothiazolones 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, non-peptide 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.

2,5-Diarylisothiazolone: novel inhibitors of cytokine-induced cartilage destruction

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.

Inhibition of cartilage breakdown by isothiazolones

Abstract Isothiazolones and isoselenazolones have been found to inhibit IL-1β induced breakdown of bovine nasal cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, non-peptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease.

Vinylogous hydroxamic acids: 5-lipoxygenase inhibitors

Abstract Vinylogous hydroxamic acids were prepared as inhibitors of 5-lipoxygenase. The synthesis and preliminary SAR of these relatively unexplored compounds are described. These compounds are potent 5-lipoxygenase inhibitors which do not inhibit other enzymes of the arachidonic acid cascade.

Inhibition of cartilage degradation by isothiazoloquinolinones

Abstract Several aryl-fused isothiazoloquinolinones were prepared and were found to inhibit IL-1β induced degradation of bovine nasal cartilage in an organ culture assay. These compounds, derived conceptually from the benzisothiazolone ring system, represent a new, non-peptide class of inhibitors of cartilage degradation.