ABSTRACT
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.
Subject(s)
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 RelationshipABSTRACT
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.
Subject(s)
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Factor VIIa/antagonists & inhibitors , Thrombosis/drug therapy , Administration, Oral , Animals , Biological Availability , Rats , Structure-Activity Relationship , Thrombin/antagonists & inhibitorsABSTRACT
The discovery and development of 5-azaindole factor VIIa inhibitors will be described.
Subject(s)
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 RelationshipABSTRACT
Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold.
Subject(s)
Aminopyridines/chemistry , Factor VIIa/antagonists & inhibitors , Fibrinolytic Agents/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Thromboplastin/antagonists & inhibitors , Aminopyridines/pharmacology , Binding Sites , Crystallography, X-Ray , Drug Design , Fibrinolytic Agents/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.
