The 4-amino-5-azaindole as an amidino-benzimidazole replacement is described. A series of potent and selective analogs were discovered and showed desirable ex vivo efficacy as measured by PT.
Factor VIIa/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Factor VIIa/metabolism , Indoles/chemistry , Molecular Structure , Pyridines/chemistry , Structure-Activity Relationship
Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Factor VIIa/antagonists & inhibitors , Thrombosis/drug therapy , Administration, Oral , Animals , Biological Availability , Rats , Structure-Activity Relationship , Thrombin/antagonists & inhibitors
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Factor VIIa/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Aza Compounds/chemistry , Crystallography, X-Ray , Factor VIIa/chemistry , Factor VIIa/metabolism , Indoles/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
Efforts to improve the potency and pharmacokinetic properties of small molecule factor VIIa inhibitors are described. Small structural modifications to existing leads allow the modulation of half-life and clearance, potentially making these compounds suitable candidates for drug development.
Anticoagulants/pharmacokinetics , Blood Coagulation/drug effects , Factor VIIa/antagonists & inhibitors , Serine Proteinase Inhibitors/pharmacokinetics , Animals , Drug Design , Half-Life , Humans , Molecular Structure , Structure-Activity Relationship
Highly selective and potent factor VIIa-tissue factor (fVIIa.TF) complex inhibitors were generated through structure-based design. The pharmacokinetic properties of an optimized analog (9) were characterized in several preclinical species, demonstrating pharmacokinetic characteristics suitable for once-a-day dosing in humans. Analog 9 inhibited platelet and fibrin deposition in a dose-dependent manner after intravenous administration in a baboon thrombosis model, and a pharmacodynamic concentration-response model was developed to describe the platelet deposition data. Results for heparin and enoxaparin (Lovenox) in the baboon model are also presented.
Factor VIIa/antagonists & inhibitors , Models, Animal , Serine Proteinase Inhibitors/pharmacology , Thrombosis/drug therapy , Animals , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Models, Molecular , Papio , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/therapeutic use
Modulation of the acetylation state of histones plays a pivotal role in the regulation of gene expression. Histone deacetylases (HDACs) catalyze the removal of acetyl groups from lysines near the N termini of histones. This reaction promotes the condensation of chromatin, leading to repression of transcription. HDAC deregulation has been linked to several types of cancer, suggesting a potential use for HDAC inhibitors in oncology. Here we describe the first crystal structures of a human HDAC: the structures of human HDAC8 complexed with four structurally diverse hydroxamate inhibitors. This work sheds light on the catalytic mechanism of the HDACs, and on differences in substrate specificity across the HDAC family. The structure also suggests how phosphorylation of Ser39 affects HDAC8 activity.
Histone Deacetylases/chemistry , Repressor Proteins/chemistry , Amino Acid Sequence , Binding Sites , Crystallography, X-Ray , Histone Deacetylases/metabolism , Humans , Models, Molecular , Molecular Sequence Data , Molecular Structure , Protein Conformation , Repressor Proteins/metabolism , Substrate Specificity
