Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression

  • Bioorg Med Chem. 2013 Apr 15;21(8):2217-2228. doi: 10.1016/j.bmc.2013.02.010.
Yong-Jin Wu  1 ,  Huan He  2 ,  Robert Bertekap  3 ,  Ryan Westphal  3 ,  Snjezana Lelas  3 ,  Amy Newton  3 ,  Tanya Wallace  3 ,  Matthew Taber  3 ,  Carl Davis  4 ,  John E Macor  2 ,  Joanne Bronson  2
Affiliations
  • 1. Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
  • 2. Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 3. Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
  • 4. Department of Preclinical Candidate Optimization, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
PMID: 23477943 DOI: 10.1016/j.bmc.2013.02.010
Abstract

This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.