Pyridazinoquinolinetriones as NMDA glycine-site antagonists with oral antinociceptive activity in a model of neuropathic pain.
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.
Bare
Thomas M
TM
AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington, Delaware 19803, USA.
Brown
Dean G
DG
Horchler
Carey L
CL
Murphy
Megan
M
Urbanek
Rebecca A
RA
Alford
Vernon
V
Barlaam
Christine
C
Dyroff
Martin C
MC
Empfield
James B
JB
Forst
Janet M
JM
Herzog
Keith J
KJ
Keith
Richard A
RA
Kirschner
Alan S
AS
Lee
Chi-Ming C
CM
Lewis
Joseph
J
McLaren
Frances M
FM
Neilson
Kathy L
KL
Steelman
Gary B
GB
Trivedi
Shephali
S
Vacek
Edward P
EP
Xiao
Wenhua
W
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
D000480:Alkynes; D000700:Analgesics; D011724:Pyridazines; D011725:Pyridines; D011804:Quinolines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate