Identification of a 5-HT4 receptor antagonist clinical candidate through side-chain modification

Bioorg Med Chem Lett. 2005 Mar 15;15(6):1697-700. doi: 10.1016/j.bmcl.2005.01.039.


Replacement of the N-butyl side-chain of lead 5-HT4 receptor antagonist 2 with propanesulfonylpiperidinyl, morpholinyl, and piperazinyl groups led to higher affinity analogs 4-6. In vitro drug metabolism screens and cassette pharmacokinetic studies in the dog led to identification of the N-methylpiperazinyl analog (6b), which displayed pharmacokinetic, selectivity, and safety parameters sufficient for advancement to the clinic for the treatment of urinary incontinence.

MeSH terms

  • Animals
  • Dogs
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Heterocyclic Compounds, 2-Ring / pharmacokinetics
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Mice
  • Models, Chemical
  • Molecular Structure
  • Rats
  • Serotonin 5-HT4 Receptor Antagonists*
  • Structure-Activity Relationship
  • Swine
  • Swine, Miniature


  • Heterocyclic Compounds, 2-Ring
  • Serotonin 5-HT4 Receptor Antagonists