Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability

  • Bioorg Med Chem Lett. 2008 Aug 15;18(16):4491-4. doi: 10.1016/j.bmcl.2008.07.049.
Sarah Hudson  1 ,  Mehrak Kiankarimi ,  Wendy Eccles ,  Wesley Dwight ,  Yalda S Mostofi ,  Marc J Genicot ,  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. [email protected]
PMID: 18672364 DOI: 10.1016/j.bmcl.2008.07.049
Abstract

The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.