ABSTRACT
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Subject(s)
Carboxylic Acids/chemistry , Drug Discovery , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Benzamidines , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor VIIa/metabolism , Humans , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/chemical synthesis , Structure-Activity RelationshipABSTRACT
Azetidinones such as BMS-363131 (2) and BMS-363130 (3), which contain a guanidine group in the C-3 side chain were previously shown to be very potent inhibitors of human tryptase with high selectivity versus other serine proteases, including trypsin. In this letter, we describe the discovery of a number of potent azetidinone tryptase inhibitors in which the guanidine moiety at the ring C-3 position is replaced with primary or secondary amine or aminopyridine functionality. In particular, BMS-354326 (4) is a highly potent tryptase inhibitor (IC(50)=1.8 nM), which has excellent selectivity against trypsin and most other related serine proteases.
Subject(s)
Azetidines/chemical synthesis , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Azetidines/chemistry , Azetidines/pharmacology , Humans , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , TryptasesABSTRACT
A series of N1-activated C4-carboxy azetidinones was prepared and tested as inhibitors of human tryptase. The key stereochemical and functional features required for potency, serine protease specificity and aqueous stability were determined. From these studies compound 2, BMS-262084, was identified as a potent and selective tryptase inhibitor which, when dosed intratracheally in ovalbumin-sensitized guinea pigs, reduced allergen-induced bronchoconstriction and inflammatory cell infiltration into the lung.
Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Animals , Asthma/drug therapy , Asthma/pathology , Bronchoconstriction/drug effects , Crystallography, X-Ray , Extracellular Space/drug effects , Guinea Pigs , Half-Life , Humans , Inflammation/pathology , Lung/pathology , Molecular Conformation , Ovalbumin/immunology , Structure-Activity Relationship , TryptasesABSTRACT
The serine protease tryptase has been implicated in allergic and inflammatory diseases and associated with asthma. The synthesis and SAR of a series of N1-activated-4-carboxy azetidinones are described, resulting in identification of BMS-363131 (2) as a potent inhibitor of human tryptase (IC(50)<1.7 nM) with high selectivity (>3000-fold) for tryptase versus related serine proteases including trypsin.
