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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2000-10, Vol.10 (20), p.2361-2366
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(00)00485-6