Structure-activity relationships of the cycloalkanol ethylamine scaffold: discovery of selective norepinephrine reuptake inhibitors.
Further exploration of the cycloalkanol ethylamine scaffold, of which venlafaxine ( 1) is a member, was undertaken to develop novel and selective norepinephrine reuptake inhibitors (NRIs) for evaluation in a variety of predictive animal models. These efforts led to the discovery of a piperazine-containing analogue, 17g (WY-46824), that exhibited potent norepinephrine reuptake inhibition, excellent selectivity over the serotonin transporter, but no selectivity over the dopamine transporter. Synthesis and testing of a series of cyclohexanol ethylpiperazines identified ( S)-(-)- 17i (WAY-256805), a potent norepinephrine reuptake inhibitor (IC 50 = 82 nM, K i = 50 nM) that exhibited excellent selectivity over both the serotonin and dopamine transporters and was efficacious in animal models of depression, pain, and thermoregulatory dysfunction.
Mahaney
Paige E
PE
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. mahanep@wyeth.com
Gavrin
Lori K
LK
Trybulski
Eugene J
EJ
Stack
Gary P
GP
Vu
T An
TA
Cohn
Stephen T
ST
Ye
Fei
F
Belardi
Justin K
JK
Santilli
Arthur A
AA
Sabatucci
Joseph P
JP
Leiter
Jennifer
J
Johnston
Grace H
GH
Bray
Jenifer A
JA
Burroughs
Kevin D
KD
Cosmi
Scott A
SA
Leventhal
Liza
L
Koury
Elizabeth J
EJ
Zhang
Yingru
Y
Mugford
Cheryl A
CA
Ho
Douglas M
DM
Rosenzweig-Lipson
Sharon J
SJ
Platt
Brian
B
Smith
Valerie A
VA
Deecher
Darlene C
DC
D000818:Animals; D002460:Cell Line; D003511:Cyclohexanols / Q000737:chemistry*; D005021:Ethylamines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009638:Norepinephrine / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism
D003511:Cyclohexanols; D005021:Ethylamines; D027981:Symporters; D009638:Norepinephrine; C041564:ethylamine