Inhibitors of cathepsin C (dipeptidyl peptidase I).
BACKGROUND
Cathepsin C (dipeptidyl peptidase I) plays a key role in the activation of several degradative enzymes linked to tissue destruction in inflammatory diseases. Thus, cathepsin C inhibitors could potentially be effective therapeutics for the treatment of such diseases as chronic obstructive pulmonary disease and cystic fibrosis.


METHODS
Although this article focuses on cathepsin C inhibitor patents, the journal literature concerning small molecule inhibitors of the enzyme is also covered comprehensively (1981 - 2009).


RESULTS
It is our aim to give the reader a complete overview of the cathepsin C inhibitor chemotypes that have been disclosed to date. In addition, key biological data have been included for both irreversible and reversible inhibitors.


CONCLUSIONS
All known cathepsin C inhibitors are believed to have a covalent interaction with the Cys-234 residue of the enzyme. The electrophilic and sometimes peptidic nature of these molecules is associated with poor metabolic stability and is also a potential safety concern. Thus, overcoming developability issues is a serious hurdle for these compounds and there can be little doubt that this is the principal reason why no cathepsin C inhibitors appear to have reached clinical development so far.
Laine
Dramane I
DI
GlaxoSmithKline, Respiratory CEDD, King of Prussia, PA 19406, USA. Dramane.I.Laine@gsk.com
Busch-Petersen
Jakob
J
D000818:Animals; D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D010330:Patents as Topic; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology
D020789:Cathepsin C