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

  • Bioorg Med Chem Lett. 2012 Oct 1;22(19):6048-52. doi: 10.1016/j.bmcl.2012.08.051.
Daniel D Long  1 ,  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
Affiliations
  • 1. Theravance, Inc., 901 Gateway Blvd, South San Francisco, CA 94080, United States. [email protected]
PMID: 22959244 DOI: 10.1016/j.bmcl.2012.08.051
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.

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