title: Substituted analogues of GV150526 as potent glycine binding site antagonists in animal models of cerebral ischemia.
abstract: A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.
authors.affiliation: Medicines Research Centre, Glaxo Wellcome S.p.A., Via Fleming 4, 37100 Verona, Italy. rdf26781@Glaxo.Wellcome.co.uk
authors.forename: R
authors.initials: R
authors.lastname: Di Fabio
authors.forename: N
authors.initials: N
authors.lastname: Conti
authors.forename: E
authors.initials: E
authors.lastname: De Magistris
authors.forename: A
authors.initials: A
authors.lastname: Feriani
authors.forename: S
authors.initials: S
authors.lastname: Provera
authors.forename: F M
authors.initials: FM
authors.lastname: Sabbatini
authors.forename: A
authors.initials: A
authors.lastname: Reggiani
authors.forename: L
authors.initials: L
authors.lastname: Rovatti
authors.forename: R J
authors.initials: RJ
authors.lastname: Barnaby
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy*; D002264:Carboxylic Acids; D002544:Cerebral Infarction / Q000188:drug therapy; D004195:Disease Models, Animal; D005998:Glycine / Q000378:metabolism; D018684:Glycine Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C121666:3-(2-((4-ureidomethylphenyl)aminocarbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D000927:Anticonvulsants; D002264:Carboxylic Acids; D018684:Glycine Agents; D007211:Indoles; D018696:Neuroprotective Agents; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C058980:indole-2-carboxylic acid; D014508:Urea; D005998:Glycine