title: 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.affiliation: Department of Medicinal Chemistry, Axys Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Rice
authors.forename: V R
authors.initials: VR
authors.lastname: Wang
authors.forename: A R
authors.initials: AR
authors.lastname: Gangloff
authors.forename: E Y
authors.initials: EY
authors.lastname: Kuo
authors.forename: J M
authors.initials: JM
authors.lastname: Dener
authors.forename: W S
authors.initials: WS
authors.lastname: Newcomb
authors.forename: W B
authors.initials: WB
authors.lastname: Young
authors.forename: D
authors.initials: D
authors.lastname: Putnam
authors.forename: L
authors.initials: L
authors.lastname: Cregar
authors.forename: M
authors.initials: M
authors.lastname: Wong
authors.forename: P J
authors.initials: PJ
authors.lastname: Simpson
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy; D003959:Diamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D018927:Anti-Asthmatic Agents; D003959:Diamines; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053802:Tryptases