Dibasic inhibitors of human mast cell tryptase. Part 2: structure-activity relationships and requirements for potent activity.

Abstract

Detailed structure activity relationships (SARs) for a series of dibasic human tryptase inhibitors are presented. The structural requirements for potent inhibitory activity are remarkably broad with a range of core template modifications being well tolerated. Optimized inhibitors demonstrate potent anti-asthmatic activity in a sheep model of allergic asthma. APC-2059, a dibasic tryptase inhibitor with subnanomolar activity, has been advanced to phase II clinical trials for the treatment of both psoriasis and ulcerative colitis.

• Authors: K D Rice, V R Wang, A R Gangloff, E Y Kuo, J M Dener, W S Newcomb, W B Young, D Putnam, L Cregar, M Wong, P J Simpson
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 10 Issue 20 Pg. 2361-6 (Oct 16 2000) ISSN: 0960-894X [Print] England
• PMID: 11055356 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Asthmatic Agents
• Diamines
• Serine Proteinase Inhibitors
• Serine Endopeptidases
• Tryptases

Topics

• Animals
• Anti-Asthmatic Agents (chemical synthesis, chemistry, pharmacology)
• Asthma (drug therapy)
• Diamines (chemical synthesis, chemistry, pharmacology)
• Disease Models, Animal
• Humans
• Kinetics
• Molecular Structure
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Sheep
• Structure-Activity Relationship
• Tryptases