Structure-activity relationships of norepinephrine reuptake inhibitors with benzothiadiazine dioxide or dihydrosulfostyril cores.
Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure-activity relationships were determined for the series' in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.
Pfizer Global Research and Development, 500 Arcola Road, Collegeville, PA 19426, USA.
Andrew
A
Fensome
Joel
J
Goldberg
Casey C
CC
McComas
Eugene J
EJ
Trybulski
Richard P
RP
Woodworth
Darlene C
DC
Deecher
Garth T
GT
Whiteside
Puwen
P
Zhang
D018759:Adrenergic Uptake Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001581:Benzothiadiazines / Q000737:chemistry*; D001692:Biological Transport; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D023421:Models, Animal; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013843:Thiazines; D009638:Norepinephrine