Structure–activity relationships and in vivo activity of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 15; pp. 4653 - 4656
• Main Authors: Beswick, Paul J., Billinton, Andy, Chambers, Laura J., Dean, David K., Fonfria, Elena, Gleave, Robert J., Medhurst, Stephen J., Michel, Anton D., Moses, Andrew P., Patel, Sadhana, Roman, Shilina A., Roomans, Sue, Senger, Stefan, Stevens, Alexander J., Walter, Daryl S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.08.2010; Elsevier
• Subjects: Analgesics; Biological and medical sciences; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; P2X7; Pain; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; SAR; P2X7; SAR; Pain; Rat; Nitrogen heterocycle; Hyperalgesia; Structure activity relation; Chlorine Organic compounds; Pyrazole derivatives; Antagonist; Human; Rodentia; Benzene derivatives; Oral administration; P2X7 purinergic receptor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Analgesic; Animal; P2X; Affinity; Carboxamide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.107

Structure–activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund’s adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res.1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain2006, 10, 537].