ABSTRACT
Among all heterocycles, the heterocycle-fused quinolinone scaffold is one of the privileged structures in drug discovery as heterocycle-fused quinolinone derivatives exhibit various biological activities allowing them to act as anti-inflammatory, anticancer, antidiabetic, and antipsychotic agents. This wide spectrum of biological activity has attracted a great deal of attention in the field of medicinal chemistry. In this review, we provide a comprehensive description of the biological and pharmacological properties of various heterocycle-fused quinolinone scaffolds and discuss the synthetic methods of some of their derivatives.
Subject(s)
Drug Discovery , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Quinolones/chemistry , Quinolones/pharmacology , Animals , HumansABSTRACT
Optimization of the pharmacokinetic properties for a series of benzoxazolone derivatives led to the identification of 9b, which showed anxiolytic effect in a rat model. However, 9b, like known benzodiazepines, induced motor impairment. Investigation into the cause of this unexpected side effect and management of 9b off-target binding affinity led to the identification of 10d, which showed oral anxiolytic effect in the rat model with improved safety profile.
Subject(s)
Anti-Anxiety Agents/pharmacology , Benzoxazoles/pharmacology , Carrier Proteins/agonists , Administration, Oral , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacokinetics , Area Under Curve , Avoidance Learning/drug effects , Benzoxazoles/chemistry , Benzoxazoles/pharmacokinetics , Carrier Proteins/chemistry , Cell Line, Tumor , Conflict, Psychological , Humans , Ligands , Male , Mice , Molecular Structure , Motor Activity/drug effects , Protein Binding , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, GABA-A/chemistry , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
The 18 kDa translocator protein (TSPO) was identified as a discrete receptor for diazepam (1). Since TSPO in the central nervous system (CNS) is believed to regulate neurosteroids biosynthesis, selective TSPO ligands are expected to be useful in the treatment of psychiatric disorders. We synthesized three novel tricyclic benzimidazolone derivatives, and selected the dihydroimidazoquinolinone derivative 27 as a lead TSPO ligand. Study of the structure-activity relationship (SAR) of dihydroimidazoquinolinone derivatives revealed compounds with potent affinity for TSPO (subnanomolar K(i) values), but poor metabolic stability. The optimization of these compounds led to compound 48 with potent affinity for TSPO and good in vitro PK profile.
Subject(s)
Acetanilides/chemical synthesis , Benzimidazoles/chemistry , Carrier Proteins/chemistry , Drug Design , Heterocyclic Compounds, 3-Ring/chemical synthesis , Receptors, GABA-A/chemistry , Acetanilides/chemistry , Acetanilides/pharmacokinetics , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Carrier Proteins/metabolism , Half-Life , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Ligands , Male , Mice , Protein Binding , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/metabolism , Structure-Activity RelationshipABSTRACT
Selective 18 kDa translocator protein (TSPO) ligands are expected to be therapeutic agents with a wide spectrum of action on psychiatric disorders and fewer side effects. We designed novel benzoxazolone derivatives and examined the structure-activity relationship (SAR) of a series of compounds with various substituents at the amide part and C-5 position. Although a number of the synthesized compounds showed high TSPO binding affinity, these compounds had poor drug-like properties. Further optimization of pharmacokinetic properties of these compounds led to discovery of compound 74, which exhibited anxiolytic effect in the rat Vogel conflict model.
Subject(s)
Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacology , Carrier Proteins/metabolism , Drug Design , Receptors, GABA-A/metabolism , Animals , Benzoxazoles/chemistry , Carrier Proteins/chemistry , Dose-Response Relationship, Drug , Ligands , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Receptors, GABA-A/chemistry , Structure-Activity RelationshipABSTRACT
Chiral nucleophilic catalysts 5-15 were prepared starting from L-proline. Catalysts 9 and 14 promoted acylative kinetic resolution of racemic amino alcohol derivative 16 with selectivity factors of 8.1 and 11, respectively, at ambient temperature. Since chiral elements are not present in the catalytically active pyridine ring in these catalysts, chirality transfer from the remote stereogenic center to the reactive site (N-acylpyridinium) is suggested to be responsible for the differentiation between enantiomers.
