ABSTRACT
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats.
Subject(s)
Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Glycine/analogs & derivatives , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombin III/chemistry , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Glycine/chemical synthesis , Glycine/chemistry , Glycine/pharmacology , Humans , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
A vinyl azide cyclization method was used to synthesize three different carbocyclic[g]indole scaffolds as inhibitors of human nonpancreatic secretory phospholipase A2. Each scaffold demonstrated potent enzyme activity in a chromogenic assay system, with select examples also demonstrating potent activity in a secondary DOC/PC assay. Compound 11, representative of the cyclopent[g]indole series, gave an IC50 of 10 nM for the inhibition of hnps-PLA2 in the chromogenic assay.
