Structure-activity relationships of chiral selective norepinephrine reuptake inhibitors (sNRI) with increased oxidative stability.
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.
Hudson
Sarah
S
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. shudson@neurocrine.com
Kiankarimi
Mehrak
M
Eccles
Wendy
W
Dwight
Wesley
W
Mostofi
Yalda S
YS
Genicot
Marc J
MJ
Fleck
Beth A
BA
Gogas
Kathleen
K
Aparicio
Anna
A
Wang
Hua
H
Wen
Jenny
J
Wade
Warren S
WS
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000069445:Atomoxetine Hydrochloride; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009638:Norepinephrine / Q000737:chemistry* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D010100:Oxygen / Q000737:chemistry*; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D027981:Symporters / Q000737:chemistry
D018759:Adrenergic Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; D027981:Symporters; D000069445:Atomoxetine Hydrochloride; D019389:Cytochrome P-450 CYP2D6; D010100:Oxygen; D009638:Norepinephrine