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
A series of acylguanidine derivatives were prepared and investigated as inhibitors of Factor Xa (FXa). These compounds were made by guanidine acylation with carboxylic acids using carbonyl diimidazole (CDI) as the coupling reagent. Conditions for the rapid synthesis and purification of these compounds are described along with their ability to inhibit FXa. The best FXa inhibitor is 1 with a FXa IC(50) of 6 nM.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Chemistry, Pharmaceutical/methods , Factor Xa/chemistry , Guanidines/chemical synthesis , Guanidines/pharmacology , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Blood Coagulation , Carboxylic Acids/chemistry , Drug Design , Guanine/chemistry , Humans , Imidazoles/chemistry , Inhibitory Concentration 50 , Models, Chemical , Molecular StructureABSTRACT
N,N'-Disubstituted ketene aminals are good bioisosteres of thiourea functional groups. We report the design and synthesis of a novel class of ketene aminal-based lactam derivatives as potent and orally active FXa inhibitors.
Subject(s)
Ethylenes/pharmacology , Factor Xa Inhibitors , Ketones/pharmacology , Lactams/pharmacology , Administration, Oral , Ethylenes/administration & dosage , Ethylenes/chemistry , Humans , Ketones/administration & dosage , Ketones/chemistry , Lactams/administration & dosage , Models, Molecular , Molecular Conformation , 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 nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered.
Subject(s)
Azetidines/chemical synthesis , Azetidines/pharmacology , Serine Endopeptidases/drug effects , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Azetidines/chemistry , Crystallography, X-Ray , Models, Molecular , Serine Endopeptidases/chemistry , Serine Proteinase Inhibitors/chemistry , Structure-Activity Relationship , TryptasesABSTRACT
The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
Subject(s)
Azepines/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Azepines/pharmacology , Humans , Serine Proteinase Inhibitors/pharmacology , TryptasesABSTRACT
Protease activated receptor-1 (PAR-1) is a G-coupled receptor cleaved by thrombin and other proteases to expose a new N-terminus, a "tethered ligand", that activates the receptor. Independently of proteolytic cleavage, peptides similar to the new N-terminus also activate the receptor, and structure activity relationships for the activating peptides have been extensively studied. Modification of activating peptides led to rationally designed peptide antagonists. The more potent peptide antagonists were N-terminal and 3-position modifications of the agonist peptides. The resulting PAR-1 antagonists have proved useful in pharmacological studies resolving the contribution of PAR-1 signaling mechanisms relative to other PARs in platelets, vascular endothelial and other cell types. High affinity peptide agonists and antagonists have been radiolabled and proven useful in binding assays. Screening of combinatorial libraries and compound collections using the radioligands have identified non-peptide antagonists of several different chemotypes. When the "thrombin receptor" (PAR-1) was first cloned and its mechanism of activation elucidated, there was great enthusiasm for the receptor as a drug target. The use of peptide agonists and antagonists has made possible much progress in our understanding of the role of this receptor.
Subject(s)
Peptides/pharmacology , Receptor, PAR-1/antagonists & inhibitors , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Mimicry , Peptides/chemistry , Platelet Aggregation Inhibitors/chemistry , Platelet Aggregation Inhibitors/pharmacology , Receptor, PAR-1/agonists , Structure-Activity RelationshipABSTRACT
A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.
Subject(s)
Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Thrombin/antagonists & inhibitors , Animals , Binding Sites/drug effects , Catalysis , Humans , Mice , Structure-Activity Relationship , Thrombin/chemistry , Thrombin/toxicityABSTRACT
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.
Subject(s)
Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Aziridines/chemical synthesis , Aziridines/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Animals , Asthma/drug therapy , Asthma/immunology , Drug Stability , Guinea Pigs , Humans , Ovalbumin/immunology , Stereoisomerism , Structure-Activity Relationship , TryptasesABSTRACT
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure- activity relationships (SAR), selectivity and activity in vivo. BMS-189090 (5) is identified as a potent, selective, and reversible inhibitor of human alpha-thrombin that is efficacious in vivo in a mice lethality model, and in inhibiting both arterial and venous thrombosis in a rat model.
Subject(s)
Serine/analogs & derivatives , Thrombin/antagonists & inhibitors , Animals , Binding Sites , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Mice , Nipecotic Acids/chemical synthesis , Nipecotic Acids/chemistry , Nipecotic Acids/pharmacology , Rats , Serine/chemical synthesis , Serine/chemistry , Serine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Substrate Specificity , Thrombin/chemistry , Thrombosis/drug therapy , Thrombosis/prevention & controlABSTRACT
A series of structurally novel small molecule inhibitors of human alpha-thrombin was prepared to elucidate their structure-activity relationships (SARs), selectivity and activity in vivo. BMS-189664 (3) is identified as a potent, selective, and orally active reversible inhibitor of human alpha-thrombin which is efficacious in vivo in a mouse lethality model, and at inhibiting both arterial and venous thrombosis in cynomolgus monkey models.