title: Discovery of novel selective norepinephrine inhibitors: 1-(2-morpholin-2-ylethyl)-3-aryl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxides (WYE-114152).
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.
authors.affiliation: Chemical Sciences, Pfizer, 500 Arcola Road, Collegeville, Pennsylvania 19426, United States. david.oneill@pfizer.com
authors.forename: David J
authors.initials: DJ
authors.lastname: O'Neill
authors.forename: Adedayo
authors.initials: A
authors.lastname: Adedoyin
authors.forename: Jenifer A
authors.initials: JA
authors.lastname: Bray
authors.forename: Darlene C
authors.initials: DC
authors.lastname: Deecher
authors.forename: Andrew
authors.initials: A
authors.lastname: Fensome
authors.forename: Joel A
authors.initials: JA
authors.lastname: Goldberg
authors.forename: Jim
authors.initials: J
authors.lastname: Harrison
authors.forename: Liza
authors.initials: L
authors.lastname: Leventhal
authors.forename: Charles
authors.initials: C
authors.lastname: Mann
authors.forename: Lilly
authors.initials: L
authors.lastname: Mark
authors.forename: Lisa
authors.initials: L
authors.lastname: Nogle
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Sullivan
authors.forename: Taylor B
authors.initials: TB
authors.lastname: Spangler
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Terefenko
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Trybulski
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Uveges
authors.forename: An
authors.initials: A
authors.lastname: Vu
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: Puwen
authors.initials: P
authors.lastname: Zhang
mesh_terms: D059787:Acute Pain / Q000188:drug therapy; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002460:Cell Line; D059350:Chronic Pain / Q000188:drug therapy; D006224:Cricetinae; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009437:Neuralgia / Q000188:drug therapy; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D013237:Stereoisomerism; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C568514:1-(2-fluorophenyl)-3-(2-(morpholin-2-yl)ethyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide; D000700:Analgesics; D052160:Benzothiazoles; D003499:Cyclic S-Oxides; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D013830:Thiadiazoles