Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors

  • J Med Chem. 2008 Jul 10;51(13):4038-49. doi: 10.1021/jm8002262.
Paige E Mahaney  1 ,  Lori K Gavrin ,  Eugene J Trybulski ,  Gary P Stack ,  T An Vu ,  Stephen T Cohn ,  Fei Ye ,  Justin K Belardi ,  Arthur A Santilli ,  Joseph P Sabatucci ,  Jennifer Leiter ,  Grace H Johnston ,  Jenifer A Bray ,  Kevin D Burroughs ,  Scott A Cosmi ,  Liza Leventhal ,  Elizabeth J Koury ,  Yingru Zhang ,  Cheryl A Mugford ,  Douglas M Ho ,  Sharon J Rosenzweig-Lipson ,  Brian Platt ,  Valerie A Smith ,  Darlene C Deecher
Affiliations
  • 1. Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. [email protected]
PMID: 18557608 DOI: 10.1021/jm8002262
Abstract

Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the Serotonin Transporter, but no selectivity over the Dopamine Transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of Depression, Pain, and thermoregulatory dysfunction.

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