Selectivity profiling of novel indene H1-antihistamines for the treatment of insomnia

A series of indene analogs of the H₁-antihistamine (?)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H₁-antihistamines with desirable selectivity over CYP enzymes, the M₁ muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.