429677-04-3Relevant articles and documents
Nonpeptide inhibitors of cathepsin G: Optimization of a novel β-ketophosphonic acid lead by structure-based drug design
Greco, Michael N.,Hawkins, Michael J.,Powell, Eugene T.,Almond Jr., Harold R.,Corcoran, Thomas W.,De Garavilla, Lawrence,Kauffman, Jack A.,Recacha, Rosario,Chattopadhyay, Debashish,Andrade-Gordon, Patricia,Maryanoff, Bruce E.
, p. 3810 - 3811 (2007/10/03)
The serine protease cathepsin G (EC 3.4.21.20; 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 A). 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. Copyright
