title: A novel class of cyclic beta-dicarbonyl leaving groups and their use in the design of benzisothiazolone human leukocyte elastase inhibitors.
abstract: Human leukocyte elastase (HLE) has been proposed to be a primary mediator of pulmonary emphysema, and inhibitors of this enzyme should be effective in the treatment of emphysema and other pulmonary diseases. We have discovered a novel class of alicyclic and heterocyclic leaving groups which share one common structural feature, a cyclic beta-dicarbonyl. This design concept for leaving groups has not been previously reported. A structure-activity relationship has been developed and the concept extended to several types of alicyclic and heterocyclic beta-dicarbonyl systems. This work led to the identification of a potent (K*i of 0.066 nM) and tissue stable (in vitro: blood t1/2 = 160 min, liver t1/2 > 240 min) benzisothiazolone HLE inhibitor, WIN 65936 (13b).
mesh_terms: D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D019272:Leukocyte Elastase; D008099:Liver / Q000378:metabolism; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D012439:Saccharin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; C096776:WIN 65936; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase; D012439:Saccharin