ABSTRACT
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.