title: A novel, potent dual inhibitor of the leukocyte proteases cathepsin G and chymase: molecular mechanisms and anti-inflammatory activity in vivo.
abstract: Certain leukocytes release serine proteases that sustain inflammatory processes and cause disease conditions, such as asthma and chronic obstructive pulmonary disease. We identified beta-ketophosphonate 1 (JNJ-10311795; RWJ-355871) as a novel, potent dual inhibitor of neutrophil cathepsin G (K(i) = 38 nm) and mast cell chymase (K(i) = 2.3 nm). The x-ray crystal structures of 1 complexed with human cathepsin G (1.85 A) and human chymase (1.90 A) reveal the molecular basis of the dual inhibition. Ligand 1 occupies the S(1) and S(2) subsites of cathepsin G and chymase similarly, with the 2-naphthyl in S(1), the 1-naphthyl in S(2), and the phosphonate group in a complex network of hydrogen bonds. Surprisingly, however, the carboxamido-N-(naphthalene-2-carboxyl)piperidine group is found to bind in two distinct conformations. In cathepsin G, this group occupies the hydrophobic S(3)/S(4) subsites, whereas in chymase, it does not; rather, it folds onto the 1-naphthyl group of the inhibitor itself. Compound 1 exhibited noteworthy anti-inflammatory activity in rats for glycogen-induced peritonitis and lipopolysaccharide-induced airway inflammation. In addition to a marked reduction in neutrophil influx, 1 reversed increases in inflammatory mediators interleukin-1alpha, interleukin-1beta, tissue necrosis factor-alpha, and monocyte chemotactic protein-1 in the glycogen model and reversed increases in airway nitric oxide levels in the lipopolysaccharide model. These findings demonstrate that it is possible to inhibit both cathepsin G and chymase with a single molecule and suggest an exciting opportunity in the treatment of asthma and chronic obstructive pulmonary disease.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Michael N
authors.initials: MN
authors.lastname: Greco
authors.forename: Narayanasami
authors.initials: N
authors.lastname: Sukumar
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Chen
authors.forename: Agustin O
authors.initials: AO
authors.lastname: Pineda
authors.forename: F Scott
authors.initials: FS
authors.lastname: Mathews
authors.forename: Enrico
authors.initials: E
authors.lastname: Di Cera
authors.forename: Edward C
authors.initials: EC
authors.lastname: Giardino
authors.forename: Grace I
authors.initials: GI
authors.lastname: Wells
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Haertlein
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kauffman
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Corcoran
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Eckardt
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053818:Chymases; D018360:Crystallography, X-Ray; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008407:Mast Cells / Q000201:enzymology; D063065:Organophosphonates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010538:Peritonitis / Q000188:drug therapy / Q000201:enzymology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C503282:JNJ-10311795; D063065:Organophosphonates; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; C509226:CMA1 protein, human; D053818:Chymases; C509228:Cma1 protein, rat