title: Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties.
abstract: The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
authors.affiliation: Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA. mmckinnell@theravance.com
authors.forename: R Murray
authors.initials: RM
authors.lastname: McKinnell
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: David T
authors.initials: DT
authors.lastname: Beattie
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fatheree
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Long
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Marquess
authors.forename: Jeng-Pyng
authors.initials: JP
authors.lastname: Shaw
authors.forename: Ross G
authors.initials: RG
authors.lastname: Vickery
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D018360:Crystallography, X-Ray; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006207:Half-Life; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry* / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: C581614:4-((4-((2-isopropyl-1H-benzoimidazole-4-carbonyl)amino)methyl)piperidin-1-ylmethyl)piperidine-1-carboxylic acid methyl ester; D001562:Benzimidazoles; D010880:Piperidines; D020033:Protein Isoforms; D058828:Serotonin 5-HT4 Receptor Agonists; D044422:Receptors, Serotonin, 5-HT4; C031000:benzimidazole