Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint

Sarah Hudson; Mehrak Kiankarimi; Wendy Eccles; Yalda S Mostofi; Marc J Genicot; Wesley Dwight; Beth A Fleck; Kathleen Gogas; Warren S Wade

doi:10.1016/j.bmcl.2008.07.050

Synthesis and structure-activity relationships of selective norepinephrine reuptake inhibitors (sNRI) with a heterocyclic ring constraint

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4495-8. doi: 10.1016/j.bmcl.2008.07.050. Epub 2008 Jul 17.

Authors

Sarah Hudson¹, Mehrak Kiankarimi, Wendy Eccles, Yalda S Mostofi, Marc J Genicot, Wesley Dwight, Beth A Fleck, Kathleen Gogas, Warren S Wade

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. shudson@neurocrine.com

PMID: 18667309
DOI: 10.1016/j.bmcl.2008.07.050

Abstract

The design, synthesis and SAR of a series of heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. As racemates, the best compounds compare favorably with atomoxetine (IC(50)'s<10 nM) in potency at the transporter.

MeSH terms

Atomoxetine Hydrochloride
Chemistry, Pharmaceutical / methods
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Drug Design
Humans
Indenes / pharmacology
Inhibitory Concentration 50
Microsomes, Liver / enzymology
Models, Chemical
Norepinephrine / chemistry
Norepinephrine / metabolism
Norepinephrine Plasma Membrane Transport Proteins / chemistry*
Norepinephrine Plasma Membrane Transport Proteins / metabolism
Propylamines / chemistry
Serotonin / chemistry
Structure-Activity Relationship

Substances

Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Indenes
Norepinephrine Plasma Membrane Transport Proteins
Propylamines
MDL 27777
Serotonin
Atomoxetine Hydrochloride
Cytochrome P-450 CYP3A
CYP3A4 protein, human
Norepinephrine