Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter

  • ACS Med Chem Lett. 2010 Mar 25;1(3):91-5. doi: 10.1021/ml100009p.
Lori K Gavrin  1 ,  Paige E Mahaney  2 ,  Douglas Jenkins  2 ,  Lisa M Nogle  2 ,  Cheryl A Mugford  3 ,  Christine Huselton  3 ,  Jennifer Leiter  4 ,  Grace H Johnston  4 ,  Jenifer A Bray  4 ,  Kevin D Burroughs  4 ,  Scott A Cosmi  4 ,  Peter Alfinito  4 ,  Douglas M Ho  5 ,  Darlene C Deecher  4 ,  Eugene J Trybulski  2
Affiliations
  • 1. Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140.
  • 2. Worldwide Medicinal Chemistry.
  • 3. Drug Safety and Metabolism.
  • 4. Women's Health and Musculoskeletal Biology.
  • 5. Department of Chemistry, Princeton University, Princeton, New Jersey 08544.
PMID: 24900182 DOI: 10.1021/ml100009p
Abstract

The potency and selectivity of a series of 1-{(1S)-2-[amino]-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol analogues are described. These compounds were prepared to improve in vitro metabolic stability and achieve brain penetration. Compound 13 (WAY-260022, NRI-022) was found to be a potent inhibitor of norepinephrine reuptake and demonstrated excellent selectivity over the serotonin and dopamine transporters. Additionally, 13 exhibited oral efficacy in a rat model of thermoregulatory dysfunction.

Keywords
WAY-260022; brain penetration, vasomotor symptoms; dopamine transporter; norepinephrine reuptake inhibitor; serotonin transporter.
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