Development of the 2nd generation neurokinin-1 receptor antagonist LY686017 for social anxiety disorder

Eur Neuropsychopharmacol. 2010 Feb;20(2):80-7. doi: 10.1016/j.euroneuro.2009.10.005. Epub 2009 Dec 16.


The neurokinin-1 (NK-1) antagonist LY686017 showed activity in preclinical anxiety models. The clinical development of LY686017 included a PET study and a proof-of-concept in social anxiety disorder (SAD). [(11)C]GR205171 was used healthy volunteers receiving 1-100mg/d LY686017 for 28 days to determine brain receptor occupancy (RO). The mean NK-1 RO increased ranged from 25% with 1mg to 93% with 100mg. Subsequently, a 12-week randomized clinical trial tested LY686017 vs. paroxetine, or placebo in SAD. Pharmacokinetic (PK)/RO modeling based on the PET results predicted that once daily dosing of >30mg LY686017 led to sustained trough RO of over 80%. 189 outpatients(1) suffering from SAD were randomly assigned to 12-weeks treatment with 50mg/d LY686017 (N=77), placebo (N=74), or 20mg/d paroxetine (N=38). There was no significant difference between LY686017 and placebo as measured with the Liebowitz Social Anxiety scale (LSAS). The active comparator paroxetine showed positive trends on primary and secondary measures. The plasma concentrations were above the level expected to produce maximal brain NK-1 RO based on the PK/RO relationship obtained in the human PET investigation. Thus, further evaluation of LY686017 for the treatment of SAD does not seem warranted.

Trial registration: NCT00191022.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology
  • Anti-Anxiety Agents / therapeutic use*
  • Anxiety Disorders / diagnostic imaging
  • Anxiety Disorders / drug therapy*
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Dose-Response Relationship, Drug
  • Gerbillinae
  • Humans
  • Male
  • Neurokinin-1 Receptor Antagonists*
  • Paroxetine / therapeutic use
  • Peptide Fragments / pharmacology
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use*
  • Radioligand Assay
  • Radionuclide Imaging
  • Receptors, Neurokinin-1 / drug effects
  • Stereotyped Behavior / drug effects
  • Substance P / analogs & derivatives
  • Substance P / pharmacology
  • Treatment Outcome
  • Triazoles / pharmacokinetics
  • Triazoles / pharmacology*
  • Triazoles / therapeutic use*


  • Anti-Anxiety Agents
  • LY686017
  • Neurokinin-1 Receptor Antagonists
  • Peptide Fragments
  • Pyridines
  • Receptors, Neurokinin-1
  • Triazoles
  • GR 73632
  • Substance P
  • Paroxetine

Associated data