title: The discovery of diazepinone-based 5-HT3 receptor partial agonists.
abstract: Serotonin type 3 (5-HT3) receptor partial agonists have been targeted as potential new drugs for the symptomatic relief of irritable bowel syndrome (IBS). Multiple diazepinone-based compounds have been discovered, which exhibit nanomolar binding affinity for the h5-HT3A receptor and display a range of intrinsic activities (IA=7-87% of 5-HT Emax) in HEK cells heterologously expressing the h5-HT3A receptor. Favorable physicochemical properties and in vitro ADME profile coupled with oral activity in the murine von Bezold-Jarisch reflex model demonstrates the series has promise for producing low to moderate IA partial agonists suitable for an IBS indication.
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States. Electronic address: David.Manning@amriglobal.com.
authors.forename: David D
authors.initials: DD
authors.lastname: Manning
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Cheng
authors.initials: C
authors.lastname: Guo
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Ryan
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Naginskaya
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Sok Hui
authors.initials: SH
authors.lastname: Choo
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Liaqat
authors.initials: L
authors.lastname: Masih
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: William G
authors.initials: WG
authors.lastname: Earley
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wierschke
authors.affiliation: Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham B15 2SQ, UK.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Newman
authors.affiliation: Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham B15 2SQ, UK.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brady
authors.affiliation: Celentyx Ltd, Birmingham Research Park, Vincent Drive, Edgbaston, Birmingham B15 2SQ, UK; Clinical and Experimental Medicine, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Barnes
authors.affiliation: Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, NY 12212-5098, United States.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Guzzo
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D051379:Mice; D015394:Molecular Structure; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D044406:Receptors, Serotonin, 5-HT3
keywords: 5-HT(3) receptor partial agonist; Alosetron; Diazepinone; Irritable bowel syndrome (IBS); Ligand-gated ion channel; Ramosetron