title: Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Greco
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Powell
authors.forename: Harold R
authors.initials: HR
authors.lastname: Almond
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Corcoran
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kauffman
authors.forename: Rosario
authors.initials: R
authors.lastname: Recacha
authors.forename: Debashish
authors.initials: D
authors.lastname: Chattopadhyay
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: 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
chemical_list: D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G