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.
Chemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. mahanep@wyeth.com
Paige E
PE
Mahaney
Lori K
LK
Gavrin
Eugene J
EJ
Trybulski
Gary P
GP
Stack
T An
TA
Vu
Stephen T
ST
Cohn
Fei
F
Ye
Justin K
JK
Belardi
Arthur A
AA
Santilli
Joseph P
JP
Sabatucci
Jennifer
J
Leiter
Grace H
GH
Johnston
Jenifer A
JA
Bray
Kevin D
KD
Burroughs
Scott A
SA
Cosmi
Liza
L
Leventhal
Elizabeth J
EJ
Koury
Yingru
Y
Zhang
Cheryl A
CA
Mugford
Douglas M
DM
Ho
Sharon J
SJ
Rosenzweig-Lipson
Brian
B
Platt
Valerie A
VA
Smith
Darlene C
DC
Deecher
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