title: Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: potential application for the treatment of irritable bowel syndrome.
abstract: Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol+ ++-3-yl] -1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED50 = 0.1 mg/kg) along with potency for normalization of GI motility (ED50 = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, a Division of Eli Lilly and Company, Lilly Corporate, Indianapolis, Indiana 46285, USA.
authors.forename: C H
authors.initials: CH
authors.lastname: Mitch
authors.forename: T J
authors.initials: TJ
authors.lastname: Brown
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: D
authors.initials: D
authors.lastname: Dieckman
authors.forename: L
authors.initials: L
authors.lastname: Merrit
authors.forename: S C
authors.initials: SC
authors.lastname: Peters
authors.forename: S J
authors.initials: SJ
authors.lastname: Quimby
authors.forename: H E
authors.initials: HE
authors.lastname: Shannon
authors.forename: L A
authors.initials: LA
authors.lastname: Shipley
authors.forename: J S
authors.initials: JS
authors.lastname: Ward
authors.forename: K
authors.initials: K
authors.lastname: Hansen
authors.forename: P H
authors.initials: PH
authors.lastname: Olesen
authors.forename: P
authors.initials: P
authors.lastname: Sauerberg
authors.forename: M J
authors.initials: MJ
authors.lastname: Sheardown
authors.forename: M D
authors.initials: MD
authors.lastname: Swedberg
authors.forename: P
authors.initials: P
authors.lastname: Suzdak
authors.forename: B
authors.initials: B
authors.lastname: Greenwood
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D003109:Colonic Diseases, Functional / Q000188:drug therapy*; D015195:Drug Design; D005289:Ferrets; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D051379:Mice; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D009619:Nociceptors / Q000187:drug effects; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D018721:Muscarinic Agonists; D010095:Oxotremorine; C042743:oxotremorine M