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

Affiliation

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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