Discovery of novel and selective tertiary alcohol containing inhibitors of the norepinephrine transporter.
A novel series of tertiary alcohol containing 2-substituted benzyl morpholines have been discovered as potent and selective inhibitors of the norepinephrine transporter. Efficient synthetic routes were developed featuring a highly diastereoselective nucleophilic addition of benzyl Grignard reagents to enantiopure (4-benzylmorpholin-2-yl)phenylmethanone (11) as the key synthetic step. In vitro binding affinity for the norepinephrine, dopamine and serotonin transporters and in vivo examination of a select compound (16) in a pharmacodynamic animal model for norepinephrine reuptake inhibition are presented.
Cases-Thomas
Manuel J
MJ
Eli Lilly and Company, Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK. cases_manuel@lilly.com
Masters
John J
JJ
Walter
Magnus W
MW
Campbell
Gordon
G
Haughton
Louise
L
Gallagher
Peter T
PT
Dobson
David R
DR
Mancuso
Vincent
V
Bonnier
Benjamin
B
Giard
Thierry
T
Defrance
Thierry
T
Vanmarsenille
Michel
M
Ledgard
Andrew
A
White
Craig
C
Ouwerkerk-Mahadevan
Sivi
S
Brunelle
Francoise J
FJ
Dezutter
Nancy A
NA
Herbots
Camy A
CA
Lienard
Joel Y
JY
Findlay
Jeremy
J
Hayhurst
Lorna
L
Boot
John
J
Thompson
Linda K
LK
Hemrick-Luecke
Susan
S
D000438:Alcohols / Q000737:chemistry*; D018360:Crystallography, X-Ray; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*
D000438:Alcohols; D050483:Dopamine Plasma Membrane Transport Proteins; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins