1-(Indolin-1-yl)-1-phenyl-3-propan-2-olamines as potent and selective norepinephrine reuptake inhibitors.
Efforts to identify new selective and potent norepinephrine reuptake inhibitors (NRIs) for multiple indications by structural modification of the previous 3-(arylamino)-3-phenylpropan-2-olamine scaffold led to the discovery of a novel series of 1-(indolin-1-yl)-1-phenyl-3-propan-2-olamines (9). Investigation of the structure-activity relationships revealed that small alkyl substitution at the C3 position of the indoline ring enhanced selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Several compounds bearing a 3,3-dimethyl group on the indoline ring, 9k, 9o,p, and 9s,t, exhibited potent inhibition of NET (IC(50) = 2.7-6.5 nM) and excellent selectivity over both serotonin and dopamine transporters. The best example from this series, 9p, a potent and highly selective NRI, displayed oral efficacy in a telemetric rat model of ovariectomized-induced thermoregulatory dysfunction, a mouse p-phenylquinone (PPQ) model of acute visceral pain, and a rat spinal nerve ligation (SNL) model of neuropathic pain.
Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. vua@wyeth.com
An T
AT
Vu
Stephen T
ST
Cohn
Puwen
P
Zhang
Callain Y
CY
Kim
Paige E
PE
Mahaney
Jenifer A
JA
Bray
Grace H
GH
Johnston
Elizabeth J
EJ
Koury
Scott A
SA
Cosmi
Darlene C
DC
Deecher
Valerie A
VA
Smith
James E
JE
Harrison
Liza
L
Leventhal
Garth T
GT
Whiteside
Jeffrey D
JD
Kennedy
Eugene J
EJ
Trybulski
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D011412:Propanolamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D007211:Indoles; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011412:Propanolamines