ABSTRACT
We have designed and synthesized a novel series of alpha-amino cyclic boronates and incorporated them successfully in several acyclic templates at the P1 position. These compounds are inhibitors of the HCV NS3 serine protease, and structural studies show that they inhibit the NS3 protease by trapping the Ser-139 hydroxyl group in the active site. Synthetic methodologies and SARs of this series of compounds are described.
Subject(s)
Boronic Acids/chemical synthesis , Hepacivirus/drug effects , Viral Nonstructural Proteins/antagonists & inhibitors , Boronic Acids/pharmacology , Boronic Acids/therapeutic use , Catalytic Domain , Drug Design , Hepacivirus/enzymology , Molecular Structure , Serine/chemistry , Structure-Activity RelationshipABSTRACT
Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
Subject(s)
Alanine/chemistry , Amides/chemistry , Antithrombin III/chemical synthesis , Antithrombin III/pharmacology , Drug Design , Pyrroles/chemistry , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/metabolism , Anticoagulants/pharmacology , Antithrombin III/chemistry , Antithrombin III/metabolism , Binding Sites , Crystallography, X-Ray , Factor Xa/chemistry , Factor Xa/metabolism , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Studies to discover novel, potent and selective oxytocin antagonists are reported. Combinatorial libraries designed to find novel replacements of fragments of oxytocin antagonist L-371,257, identified pyrimidine, thiazole, indole and benzofuran as potential alternatives to the benzoic acid moiety of L-371,257. Additional investigations identified indole and benzofuran derivatives with potent oxytocin antagonist activity.
Subject(s)
Benzofurans/chemical synthesis , Indoles/chemical synthesis , Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/antagonists & inhibitors , Animals , Benzofurans/chemistry , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , Biological Availability , Dogs , Drug Design , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/pharmacology , Kinetics , Models, Molecular , Molecular Conformation , Structure-Activity RelationshipABSTRACT
The paper covers continuing efforts to discover novel, potent and selective oxytocin antagonists. Further benzofuran derivatives with potent oxytocin antagonist activity and good pharmacokinetic parameters are reported. Efforts to improve the in vivo activity of the series are described.
