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: Daniel D Long, Scott R Armstrong, David T Beattie, Seok-Ki Choi, Paul R Fatheree, Roland A L Gendron, Daniel Genov, Adam A Goldblum, Patrick P Humphrey, Lan Jiang, Daniel G Marquess, Jeng-Pyng Shaw, Jacqueline A M Smith, S Derek Turner, Ross G Vickery
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 19 Pg. 6048-52 (Oct 01 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 22959244 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Azabicyclo Compounds
• Serotonin 5-HT4 Receptor Agonists
• TD-5108
• Receptors, Serotonin, 5-HT4

Topics

• Animals
• Azabicyclo Compounds (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Chronic Disease
• Constipation (drug therapy)
• Drug Discovery
• Guinea Pigs
• Humans
• Molecular Structure
• Rats
• Receptors, Serotonin, 5-HT4 (metabolism)
• Serotonin 5-HT4 Receptor Agonists (chemistry, pharmacokinetics, pharmacology, therapeutic use)
• Structure-Activity Relationship