title: Discovery, oral pharmacokinetics and in vivo efficacy of velusetrag, a highly selective 5-HT(4) receptor agonist that has achieved proof-of-concept in patients with chronic idiopathic constipation.
abstract: Utilization of Theravance's multivalent approach to drug discovery towards 5-HT(4) receptor agonists with a focus on identification of neutral (non-charged at physiological pH) secondary binding groups is described. Optimization of a quinolone-tropane primary binding group with a chiral 2-propanol linker to a range of neutral secondary binding group motifs, for binding affinity and functional potency at the 5-HT(4) receptor, selectivity over the 5-HT(3) receptor, oral pharmacokinetics, and in vivo efficacy in models of GI motility, afforded velusetrag (TD-5108). Velusetrag has achieved proof-of-concept in patients with chronic idiopathic constipation.
authors.affiliation: Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, United States. dlong@theravance.com
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Long
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: David T
authors.initials: DT
authors.lastname: Beattie
authors.forename: Seok-Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Paul R
authors.initials: PR
authors.lastname: Fatheree
authors.forename: Roland A L
authors.initials: RA
authors.lastname: Gendron
authors.forename: Daniel
authors.initials: D
authors.lastname: Genov
authors.forename: Adam A
authors.initials: AA
authors.lastname: Goldblum
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Humphrey
authors.forename: Lan
authors.initials: L
authors.lastname: Jiang
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Marquess
authors.forename: Jeng-Pyng
authors.initials: JP
authors.lastname: Shaw
authors.forename: Jacqueline A M
authors.initials: JA
authors.lastname: Smith
authors.forename: S Derek
authors.initials: SD
authors.lastname: Turner
authors.forename: Ross G
authors.initials: RG
authors.lastname: Vickery
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy*; D055808:Drug Discovery; D006168:Guinea Pigs; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D058828:Serotonin 5-HT4 Receptor Agonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; D058828:Serotonin 5-HT4 Receptor Agonists; C533727:TD-5108; D044422:Receptors, Serotonin, 5-HT4