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

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

doi:10.1016/s0960-894x(00)00485-6

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

Bioorg Med Chem Lett. 2000 Oct 16;10(20):2361-6. doi: 10.1016/s0960-894x(00)00485-6.

Authors

K D Rice¹, 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

Affiliation

¹ Department of Medicinal Chemistry, Axys Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.

PMID: 11055356
DOI: 10.1016/s0960-894x(00)00485-6

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Anti-Asthmatic Agents
Diamines
Serine Proteinase Inhibitors
Serine Endopeptidases
Tryptases