Abstract
Sequential modification of the previously identified 4-[3-aryl-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ols led to the identification of a new series of 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides that are potent and selective inhibitors of the norepinephrine transporter over both the serotonin and dopamine transporters. One representative compound 10b (WYE-114152) had low nanomolar hNET potency (IC(50) = 15 nM) and good selectivity for hNET over hSERT (>430-fold) and hDAT (>548-fold). 10b was additionally bioavailable following oral dosing and demonstrated efficacy in rat models of acute, inflammatory, and neuropathic pain.
MeSH terms
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Acute Pain / drug therapy
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Administration, Oral
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Benzothiazoles / chemical synthesis*
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Benzothiazoles / chemistry
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Benzothiazoles / pharmacology
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Biological Availability
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Cell Line
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Chronic Pain / drug therapy
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Cricetinae
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Cyclic S-Oxides / chemical synthesis*
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Cyclic S-Oxides / chemistry
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Cyclic S-Oxides / pharmacology
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Dogs
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Humans
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Inflammation / drug therapy
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Inflammation / physiopathology
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Injections, Intravenous
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Male
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Morpholines / chemical synthesis*
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Morpholines / chemistry
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Morpholines / pharmacology
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Neuralgia / drug therapy
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Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors*
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Rats
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Stereoisomerism
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Thiadiazoles / chemical synthesis*
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Thiadiazoles / chemistry
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Thiadiazoles / pharmacology
Substances
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1-(2-fluorophenyl)-3-(2-(morpholin-2-yl)ethyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide
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Analgesics
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Benzothiazoles
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Cyclic S-Oxides
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Morpholines
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Norepinephrine Plasma Membrane Transport Proteins
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Thiadiazoles