title: Pyridazinoquinolinetriones as NMDA glycine-site antagonists with oral antinociceptive activity in a model of neuropathic pain.
abstract: A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.
authors.affiliation: AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, Delaware 19803, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bare
authors.forename: Dean G
authors.initials: DG
authors.lastname: Brown
authors.forename: Carey L
authors.initials: CL
authors.lastname: Horchler
authors.forename: Megan
authors.initials: M
authors.lastname: Murphy
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Urbanek
authors.forename: Vernon
authors.initials: V
authors.lastname: Alford
authors.forename: Christine
authors.initials: C
authors.lastname: Barlaam
authors.forename: Martin C
authors.initials: MC
authors.lastname: Dyroff
authors.forename: James B
authors.initials: JB
authors.lastname: Empfield
authors.forename: Janet M
authors.initials: JM
authors.lastname: Forst
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Herzog
authors.forename: Richard A
authors.initials: RA
authors.lastname: Keith
authors.forename: Alan S
authors.initials: AS
authors.lastname: Kirschner
authors.forename: Chi-Ming C
authors.initials: CM
authors.lastname: Lee
authors.forename: Joseph
authors.initials: J
authors.lastname: Lewis
authors.forename: Frances M
authors.initials: FM
authors.lastname: McLaren
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Neilson
authors.forename: Gary B
authors.initials: GB
authors.lastname: Steelman
authors.forename: Shephali
authors.initials: S
authors.lastname: Trivedi
authors.forename: Edward P
authors.initials: EP
authors.lastname: Vacek
authors.forename: Wenhua
authors.initials: W
authors.lastname: Xiao
mesh_terms: D000284:Administration, Oral; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000150:complications; D008297:Male; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012584:Sciatic Nerve / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D000700:Analgesics; D011724:Pyridazines; D011725:Pyridines; D011804:Quinolines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate