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

• Published in: Bioorganic & medicinal chemistry letters 2000-10, Vol.10 (20), p.2361-2366
• Main Authors: Rice, Kenneth D, Wang, Vivian R, Gangloff, Anthony R, Kuo, Elaine Y.-L, Dener, Jeffrey M, Newcomb, William S, Young, Wendy B, Putnam, Daun, Cregar, Lynne, Wong, Martin, Simpson, Paul J
• Format: Article
• Language: English
• Subjects: Animals; Anti-Asthmatic Agents - chemical synthesis; Anti-Asthmatic Agents - chemistry; Anti-Asthmatic Agents - pharmacology; Asthma - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Diamines - chemical synthesis; Diamines - chemistry; Diamines - pharmacology; Disease Models, Animal; Humans; Kinetics; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Respiratory system; Serine Endopeptidases - metabolism; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Sheep; Structure-Activity Relationship; Tryptases
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(00)00485-6

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.