ABSTRACT
The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.
Subject(s)
Drug Discovery , Factor IXa/antagonists & inhibitors , Factor Xa Inhibitors/pharmacology , Pyrimidines/pharmacology , Dose-Response Relationship, Drug , Factor IXa/metabolism , Factor Xa Inhibitors/chemical synthesis , Factor Xa Inhibitors/chemistry , Humans , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity RelationshipABSTRACT
A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.
Subject(s)
Amidines/chemical synthesis , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemical synthesis , Amidines/chemistry , Amidines/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Factor Xa/chemistry , Humans , Models, Molecular , Rats , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thrombin/chemistry , Trypsin/chemistryABSTRACT
A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined.
Subject(s)
Factor Xa Inhibitors , Pyridines/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Administration, Oral , Animals , Biological Availability , Cattle , Dogs , Drug Design , Fibrinolytic Agents/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/pharmacology , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats , Serine Proteinase Inhibitors/pharmacokinetics , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.