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Nonpeptide Inhibitors of Cathepsin G:  Optimization of a Novel β-Ketophosphonic Acid Lead by Structure-Based Drug Design

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journal contribution
posted on 20.03.2002, 00:00 by Michael N. Greco, Michael J. Hawkins, Eugene T. Powell, Harold R. Almond,, Thomas W. Corcoran, Lawrence de Garavilla, Jack A. Kauffman, Rosario Recacha, Debashish Chattopadhyay, Patricia Andrade-Gordon, Bruce E. Maryanoff
The serine protease cathepsin G (EC; Cat G), which is stored in the azurophilic granules of neutrophils (polymorphonuclear leukocytes) and released on degranulation, has been implicated in various pathological conditions associated with inflammation. By employing high-throughput screening, we identified β-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC50 = 4.1 μM). We were fortunate to obtain a cocrystal of 1 with Cat G and solve its structure by X-ray crystallography (3.5 Å). Structural details from the X-ray analysis of 1·Cat G served as a platform for optimization of this lead compound by structure-based drug design. With the aid of molecular modeling, substituents were attached to the 3-position of the 2-naphthyl ring of 1, which occupies the S1 pocket of Cat G, to provide an extension into the hydrophobic S3 region. Thus, we arrived at analogue 7 with an 80-fold potency improvement over 1 (IC50 = 53 nM). From these results, it is evident that the β-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.