Discovery of ONO-8590580: A novel, potent and selective GABA α negative allosteric modulator for the treatment of cognitive disorders.

The identification and SAR development of a series of negative allosteric modulators of the GABA α5 receptor is described. This novel series of compounds was optimised to provide analogues with high GABA α5 binding affinity, high α5 negative allosteric modulatory activity, good functional subtype selectivity and low microsomal turnover, culminating in identification of ONO-8590580.