Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design.
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 beta-ketophosphonic acid 1 as a moderate inhibitor of Cat G (IC(50) = 4.1 microM). 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 (IC(50) = 53 nM). From these results, it is evident that the beta-ketophosphonic acid unit can form the basis for a novel class of serine protease inhibitors.
Greco
Michael N
MN
Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
Hawkins
Michael J
MJ
Powell
Eugene T
ET
Almond
Harold R
HR
Corcoran
Thomas W
TW
de Garavilla
Lawrence
L
Kauffman
Jack A
JA
Recacha
Rosario
R
Chattopadhyay
Debashish
D
Andrade-Gordon
Patricia
P
Maryanoff
Bruce E
BE
D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D008958:Models, Molecular; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D012697:Serine Endopeptidases; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G