Dual function inhibitors of relevance to chronic obstructive pulmonary disease

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 10; pp. 3177 - 3180
• Main Authors: Dou, Dengfeng, He, Guijia, Alliston, Kevin R., Groutas, William C.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.05.2011; Elsevier
• Subjects: Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Caspase-1; Catalytic Domain; Dual function; Elastase; Humans; ICE; inflammation; Inhibitor; Medical sciences; Models, Molecular; Molecular Structure; Neutrophils - enzymology; Neutrophils - metabolism; Pancreatic Elastase - metabolism; Pharmacology. Drug treatments; Protease Inhibitors - metabolism; Pulmonary Disease, Chronic Obstructive - metabolism; Respiratory system; therapeutics; Time Factors; Elastase; ICE; Inhibitor; Dual function; Caspase-1; Five membered ring; Cysteine endopeptidases; Organic carbamate; Modeling; Benzoic acid derivatives; Ester; Chlorine Organic compounds; Molecular model; Chronic obstructive pulmonary disease; Chemical synthesis; Human; Leukocyte elastase; Sulfur nitrogen heterocycle; Serine endopeptidases; Enzyme; Benzene derivatives; Enzyme inhibitor; Inhibitor enzyme complex; Ketone; In vitro; Biological activity; Peptidases; Treatment; Hydrolases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.033

A designed dual functional inhibitor was found to sequentially inhibit human neutrophil elastase and caspase-1 in vitro. The general strategy and rationale underlying the design of COPD therapeutics that possess protease inhibitory activity and are also capable of releasing a species that attenuates inflammation by inhibiting caspase-1, are described. The synthesis and in vitro biochemical evaluation of a dual function molecule that sequentially inhibits HNE and caspase-1 in a time-dependent manner is reported.