Non-basic ligands for aminergic GPCRs: The discovery and development diaryl sulfones as selective,orally bioavailable 5-HT2A receptor antagonists for the treatment of sleep disorders

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.