title: BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache.
abstract: OBJECTIVE
  Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist.
  
  
  METHODS
  BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.
  
  
  RESULTS
  BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.
  
  
  CONCLUSIONS
  BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.
authors.affiliation: BTG International Ltd., 10 Fleet Place, Limeburner Lane, London, UK. karen.maubach@btgplc.com
authors.forename: K A
authors.initials: KA
authors.lastname: Maubach
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
authors.forename: D E
authors.initials: DE
authors.lastname: Clark
authors.forename: G
authors.initials: G
authors.lastname: Fenton
authors.forename: P M
authors.initials: PM
authors.lastname: Lockey
authors.forename: K L
authors.initials: KL
authors.lastname: Clark
authors.forename: A W
authors.initials: AW
authors.lastname: Oxford
authors.forename: R M
authors.initials: RM
authors.lastname: Hagan
authors.forename: C
authors.initials: C
authors.lastname: Routledge
authors.forename: R A
authors.initials: RA
authors.lastname: Coleman
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017536:Carotid Artery, Common / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D015232:Dinoprostone / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011869:Radioligand Assay; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D015232:Dinoprostone; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D011994:Recombinant Proteins; D013449:Sulfonamides; D014665:Vasodilator Agents; C541956:N-(4-(4-(5-methoxypyridin-2-yl)phenoxymethyl)-5-methylfuran-2-carbonyl)-2-methylbenzenesulfonamide; D000096926:Benzenesulfonamides; C545650:PTGER4 protein, human