Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with improved pharmaceutical characteristics

  • Bioorg Med Chem Lett. 2008 Dec 1;18(23):6151-5. doi: 10.1016/j.bmcl.2008.10.013.
Joseph Pontillo  1 ,  Dongpei Wu ,  Brett Ching ,  Sarah Hudson ,  Marc J Genicot ,  Yinghong Gao ,  Todd Ewing ,  Beth A Fleck ,  Kathleen Gogas ,  Anna Aparicio ,  Hua Wang ,  Jenny Wen ,  Warren S Wade
Affiliations
  • 1. Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA.
PMID: 18954981 DOI: 10.1016/j.bmcl.2008.10.013
Abstract

The design synthesis and SAR of a series of chiral ring-constrained norepinephrine reuptake inhibitors with improved physicochemical properties is described. Typical compounds are potent (IC(50)s<10 nM), selective against the Other monoamine transporters, weak CYP2D6 inhibitors (IC(50)s>1 microM) and stable to oxidation by human liver microsomes. In addition, the compounds exhibit a favorable polarity profile.