Sulfonamidopyrrolidinone factor Xa inhibitors: potency and selectivity enhancements via P-1 and P-4 optimization.

Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4-aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K(i) = 2 nM) with selectivity against structurally related serine proteinases (>1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl(2)-induced carotid artery thrombosis model).

A novel series of [2-[methyl(2-phenethyl)amino]-2-oxoethyl] benzene-containing leukotriene B4 antagonists: initial structure-activity relationships.

This report describes the synthesis of a new class of LTB4 receptor antagonists containing [2-[methyl(2-phenethyl)amino]-2-oxoethyl]benzene as a key binding domain for interaction with high-affinity LTB4 receptors. In addition to this binding domain, two other structural features, an acid function and a lipophilic group, are also required by these compounds for high binding affinity. Our studies indicate that maximal binding affinity in this series is controlled by the spatial relationship of these groups relative to one another. The structure-activity relationships are discussed. The most potent compound in this chemical series, (E)-5-[2-[methyl(2-phenethyl)-amino]-2-oxoethyl]-2-(benzyloxy)cinn amic acid (32), has an IC50 of 2 nM in a guinea pig spleen cell membrane assay. In the whole-cell human neutrophils binding assay, (Z)-5-[2-[methyl-(2-phenethyl)amino]-2-oxoethyl]-2-(benzyloxy)cinn amic acid (30) was the most potent compound with an IC50 of 50 nM.

Development of a novel series of (2-quinolinylmethoxy)phenyl-containing compounds as high-affinity leukotriene D4 receptor antagonists. 4. Addition of chromone moiety enhances leukotriene D4 receptor binding affinity.

The combination of the benzopyran-4-one ring, a moiety found in the prototype leukotriene antagonist, FPL 55,712, with the (2-quinolinylmethoxy)phenyl group led to a significant increase in leukotriene receptor binding affinity. This modification resulted in a 10,000-fold improvement in binding affinity compared to FPL 55,712. Compound 7 (RG 12553), with a Ki value of 0.1 nM, has higher affinity than the natural agonist LTD4 and is one of the most potent LTD4 antagonists reported. The structure-activity relationships of this series of potent leukotriene antagonists are discussed.