ABSTRACT
A novel series of TNF inhibitors was identified based on the screening of existing MMP inhibitor libraries. Further SAR optimization led to the discovery of a novel lead compound. Its synthesis, efficacy in experimental animal models, and pharmacokinetic data are discussed.
Subject(s)
Antirheumatic Agents/chemical synthesis , Arthritis, Rheumatoid/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Antirheumatic Agents/therapeutic use , Disease Models, Animal , Drug Design , Humans , Mice , Structure-Activity RelationshipABSTRACT
Optimization of the amino acid side chain and the N-alkyl group of the sulfonamide of amino acid derived sulfonamide hydroxamates is discussed. The solid-phase synthesis of these potent inhibitors of procollagen C-proteinase (PCP) is presented. In addition, novel carboxylic acid sulfonamides were discovered to be PCP inhibitors.
Subject(s)
Amino Acids/chemistry , Bone Morphogenetic Proteins/antagonists & inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Metalloendopeptidases/antagonists & inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Sulfonamides/chemistry , Bone Morphogenetic Protein 1 , Hydroxamic Acids/chemistry , Protease Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Collagenases are involved in cartilage matrix resorption. Using bovine fetal chondrocytes isolated from physeal cartilages and separated into a distinct prehypertrophic subpopulation, we show that in serum-free culture they elaborate an extracellular matrix and differentiate into hypertrophic chondrocytes. This is characterized by expression of type X collagen and the transcription factor Cbfal and increased incorporation of 45Ca2+ in the extracellular matrix, which is associated with matrix calcification. Collagenase activity, attributable only to matrix metalloproteinase (MMP) 13 (collagenase-3), is up-regulated on differentiation. A nontoxic carboxylate inhibitor of MMP-13 prevents this differentiation; it suppresses expression of type X collagen, Cbfal, and MMP-13 and inhibits increased calcium incorporation in addition to inhibiting degradation of type II collagen in the extracellular matrix. General synthesis of matrix proteins is unaffected. These results suggest that proteolysis involving MMP-13 is required for chondrocyte differentiation that occurs as part of growth plate development and which is associated with matrix mineralization.
