ABSTRACT
Scaffold hopping from a non-basic series of 5-HT(2A) receptor antagonists developed in-house that possessed reduced activity in vivo enabled the discovery of a novel series of diaryl sulfones that gave excellent occupancy on oral dosing. Not only does this work further demonstrate that oral bioavailability of a given series can be enhanced by improving physicochemical parameters such as log P, but it corroborates the growing evidence that a protonated amine is not essential for affinity at aminergic GPCRs.
Subject(s)
Serotonin 5-HT2 Receptor Antagonists , Sulfones/chemical synthesis , Administration, Oral , Amines , Animals , Biological Availability , Drug Discovery , Humans , Ligands , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Serotonin Receptor Agonists , Sleep Wake Disorders/drug therapy , Sulfones/pharmacology , Sulfones/therapeutic useABSTRACT
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
Subject(s)
Allosteric Regulation/drug effects , GABA Agonists/chemical synthesis , GABA-A Receptor Agonists , Imidazoles/chemical synthesis , Pyridines/chemical synthesis , Animals , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , GABA Agonists/chemistry , GABA Agonists/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Ligands , Mice , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Recombinant Proteins/agonists , Structure-Activity RelationshipABSTRACT
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.
Subject(s)
Piperidines/pharmacology , Piperidines/therapeutic use , Serotonin 5-HT2 Receptor Antagonists , Sleep Initiation and Maintenance Disorders/drug therapy , Animals , Dogs , Drug Evaluation, Preclinical , Ligands , Molecular Structure , Piperidines/chemical synthesis , Rats , Structure-Activity Relationship , Time FactorsABSTRACT
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.