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

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.