Structure-activity relationship studies on N'-aryl carbohydrazide P2X7 antagonists.
Nelson DW,
Sarris K,
Kalvin DM,
Namovic MT,
Grayson G,
Donnelly-Roberts DL,
Harris R,
Honore P,
Jarvis MF,
Faltynek CR,
Carroll WA.
Abbott Laboratories, Neuroscience Research and Advanced Technology, Global Pharmaceutical Research and Development, Abbott Park, Illinois 60064-6101, USA. derek.nelson@abbott.com
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.
PMID: 18438986 [PubMed - indexed for MEDLINE]