title: Discovery of WAY-260022, a Potent and Selective Inhibitor of the Norepinephrine Transporter.
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.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Global Research and Development, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140.
authors.forename: Lori K
authors.initials: LK
authors.lastname: Gavrin
authors.affiliation: Worldwide Medicinal Chemistry.
authors.forename: Paige E
authors.initials: PE
authors.lastname: Mahaney
authors.affiliation: Worldwide Medicinal Chemistry.
authors.forename: Douglas
authors.initials: D
authors.lastname: Jenkins
authors.affiliation: Worldwide Medicinal Chemistry.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Nogle
authors.affiliation: Drug Safety and Metabolism.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Mugford
authors.affiliation: Drug Safety and Metabolism.
authors.forename: Christine
authors.initials: C
authors.lastname: Huselton
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Leiter
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Grace H
authors.initials: GH
authors.lastname: Johnston
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Jenifer A
authors.initials: JA
authors.lastname: Bray
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burroughs
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Cosmi
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Peter
authors.initials: P
authors.lastname: Alfinito
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Ho
authors.affiliation: Women's Health and Musculoskeletal Biology.
authors.forename: Darlene C
authors.initials: DC
authors.lastname: Deecher
authors.affiliation: Worldwide Medicinal Chemistry.
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Trybulski
keywords: WAY-260022; brain penetration, vasomotor symptoms; dopamine transporter; norepinephrine reuptake inhibitor; serotonin transporter