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
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.
Subject(s)
Drug Discovery , Glycine/analogs & derivatives , Oxazoles/chemistry , Oxazoles/pharmacology , PPAR alpha/agonists , Animals , Cell Line , Cricetinae , Crystallography, X-Ray , Drug-Related Side Effects and Adverse Reactions , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Glycine/toxicity , Humans , Male , Mice , Models, Molecular , Oxazoles/chemical synthesis , Oxazoles/toxicity , PPAR alpha/chemistry , PPAR alpha/genetics , Protein Structure, Tertiary , Substrate Specificity , Transcriptional Activation/drug effectsABSTRACT
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
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.
