title: 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.
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.
authors.affiliation: Merck Sharp & Dohme, Eastwick Road, Harlow, Essex CM20 2QR, UK. Tammy.Ladduwahetty@glpg.com
authors.forename: Tammy
authors.initials: T
authors.lastname: Ladduwahetty
authors.forename: Myra
authors.initials: M
authors.lastname: Gilligan
authors.forename: Alexander
authors.initials: A
authors.lastname: Humphries
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Merchant
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fish
authors.forename: George
authors.initials: G
authors.lastname: McAlister
authors.forename: Magnus
authors.initials: M
authors.lastname: Ivarsson
authors.forename: Maria
authors.initials: M
authors.lastname: Dominguez
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Angus M
authors.initials: AM
authors.lastname: MacLeod
mesh_terms: D000284:Administration, Oral; D000588:Amines; D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D012893:Sleep Wake Disorders / Q000188:drug therapy; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000588:Amines; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D058830:Serotonin 5-HT2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D013450:Sulfones