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: Lawrence de Garavilla, Michael N Greco, Narayanasami Sukumar, Zhi-Wei Chen, Agustin O Pineda, F Scott Mathews, Enrico Di Cera, Edward C Giardino, Grace I Wells, Barbara J Haertlein, Jack A Kauffman, Thomas W Corcoran, Claudia K Derian, Annette J Eckardt, Bruce P Damiano, Patricia Andrade-Gordon, Bruce E Maryanoff
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 18 Pg. 18001-7 (May 06 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15741158 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• JNJ-10311795
• Organophosphonates
• Piperidines
• Serine Proteinase Inhibitors
• Cathepsins
• Serine Endopeptidases
• CTSG protein, human
• Cathepsin G
• Ctsg protein, rat
• CMA1 protein, human
• Chymases
• Cma1 protein, rat

Topics

• Acute Disease
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, chemistry, pharmacology)
• Cathepsin G
• Cathepsins (antagonists & inhibitors, metabolism)
• Chymases
• Crystallography, X-Ray
• Humans
• Leukocytes (drug effects, enzymology)
• Male
• Mast Cells (enzymology)
• Organophosphonates (administration & dosage, chemistry, pharmacology)
• Peritonitis (drug therapy, enzymology)
• Piperidines (chemistry, pharmacology)
• Pulmonary Disease, Chronic Obstructive (drug therapy, enzymology)
• Rats
• Rats, Sprague-Dawley
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (administration & dosage, chemistry, pharmacology)