Structure-activity relationship studies on N'-aryl carbohydrazide P2X7 antagonists.
N'-aryl acyl hydrazides were identified as P2X7 receptor antagonists. Structure-activity relationship (SAR) studies evaluated functional activity by monitoring calcium flux inhibition in cell lines expressing recombinant human and rat P2X7 receptors. Selected analogs were assayed in vitro for their capacity to inhibit release of cytokine IL-1beta. Compounds with potent antagonist function were evaluated in vivo using the zymosan-induced peritonitis model. A representative compound effectively attenuated mechanical allodynia in a rat model of neuropathic pain.
Nelson
Derek W
DW
Abbott Laboratories, Neuroscience Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Park, Illinois 60064-6101, USA. derek.nelson@abbott.com
Sarris
Kathy
K
Kalvin
Douglas M
DM
Namovic
Marian T
MT
Grayson
George
G
Donnelly-Roberts
Diana L
DL
Harris
Richard
R
Honore
Prisca
P
Jarvis
Michael F
MF
Faltynek
Connie R
CR
Carroll
William A
WA
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D010529:Peritoneal Cavity; D010538:Peritonitis / Q000378:metabolism / Q000517:prevention & control; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D000700:Analgesics; D006834:Hydrazines; D053583:Interleukin-1beta; D007546:Isoquinolines; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D002118:Calcium