Synthesis and SAR development of novel P2X₇ receptor antagonists for the treatment of pain: Part 1

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 12; pp. 3805 - 3808
• Main Authors: Matasi, Julius J, Brumfield, Stephanie, Tulshian, Deen, Czarnecki, Michael, Greenlee, William, Garlisi, Charles G, Qiu, Hongchen, Devito, Kristine, Chen, Shu-Cheng, Sun, Youngliang, Bertorelli, Rosalia, Geiss, William, Le, Van-Duc, Martin, Gregory S, Vellekoop, Samuel A, Haber, James, Allard, Melissa L
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.06.2011; Elsevier
• Subjects: Administration, Oral; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Animals; antagonists; Biological and medical sciences; Disease Models, Animal; Drug Design; Humans; Medical sciences; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; pain; Pain - drug therapy; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; pharmacokinetics; Pharmacology. Drug treatments; Purinergic P2 Receptor Antagonists - chemical synthesis; Purinergic P2 Receptor Antagonists - chemistry; Rats; Receptors, Purinergic P2X7 - metabolism; Structure-Activity Relationship; structure-activity relationships; Human; Biological fluid; Purine derivatives; Rat; Rodentia; Oral administration; P2X7 purinergic receptor; Neuropathic pain; Whole blood; Vertebrata; Mammalia; Analgesic; Structure activity relation; Animal; P2X; Antagonist; Pharmacokinetics; Chemical synthesis; Inflammatory pain
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.034

Structure–activity relationship (SAR) efforts around our initial lead compound 1 led to the identification of potent P2X₇ receptor antagonists with improved pharmacokinetic profiles. These compounds were potent and selective at the P2X₇ receptor in both human and rodent. Compound (entry 31) exhibited oral efficacy in the rat MIA and CCI pain models.