Structure-activity relationships of the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ol series of monoamine reuptake inhibitors.
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Mahaney
Paige E
PE
Chemical Sciences, Wyeth Research, Collegeville, PA 19426, United States. paige.mahaney@boehringeringelheim.com
Kim
Callain Y
CY
Coghlan
Richard D
RD
Cohn
Stephen T
ST
Heffernan
Gavin D
GD
Huselton
Christine A
CA
Terefenko
Eugene A
EA
Vu
An T
AT
Zhang
Puwen
P
Burroughs
Kevin D
KD
Cosmi
Scott A
SA
Bray
Jenifer A
JA
Johnston
Grace H
GH
Deecher
Darlene C
DC
Trybulski
Eugene J
EJ
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D023421:Models, Animal; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018759:Adrenergic Uptake Inhibitors; D007211:Indoles; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors