Pulmonary-Allergy, Dermatological, Gastrointestinal & Arthritis: Method of preventing neutrophil-mediated connective tissue damage

Abstract

AbstractThis patent application describes the ability of a polysulphonic acid oligomer to prevent connective tissue damage through the inhibition of two enzymes located in primary granules of human neutrophils: elastase [1] and cathepsin G [2]. These two serine proteases when released upon extreme activation have been implicated in the destruction of connective tissues such as elastin, fibronectin, collagen and proteoglycan. Normally a balance between elastase and its natural inhibitors in plasma [3] and on mucosal services [4] is maintained. However, when the balance between protease and inhibitor is disturbed, the resultant connective damage has been observed in disease states such as emphysema [5], adult respiratory distress syndrome [6], cystic fibrosis [7] and arthritis [8]. The preferred compound is a disulphonic acid biphenyl oligomer [MDL-101,028, Mn = 2500] which exhibited potent inhibitory activity in vitro against elastase and cathepsin G. In addition, protective effects were demonstrated against cartilage degradation and in a rat model of elastase-induced pulmonary damage. MDL-101,028 was prepared in a single step from the condensation of toluidine, 4,4′-diamino-(1,1′-biphenyl)-2,2′-disulphonic acid and phosgene [101].