Discovery, oral pharmacokinetics and in vivo efficacy of a highly selective 5-HT4 receptor agonist: clinical compound TD-2749

  • Bioorg Med Chem Lett. 2012 Jul 15;22(14):4849-53. doi: 10.1016/j.bmcl.2012.05.034.
Daniel D Long  1 ,  Scott R Armstrong ,  David T Beattie ,  Seok-Ki Choi ,  Paul R Fatheree ,  Roland A L Gendron ,  Adam A Goldblum ,  Patrick P Humphrey ,  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, USA. [email protected]
PMID: 22683222 DOI: 10.1016/j.bmcl.2012.05.034
Abstract

Further application of our multivalent approach to drug discovery directed to 5-HT(4) receptor agonists is described. Optimization of the linker and secondary binding amine in the indazole-tropane primary binding group series, 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, resulted in the identification of clinical compound TD-2749.

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