Synthesis and structure-activity relationships of a series of (1H-pyrazol-4-yl)acetamide antagonists of the P2X7 receptor

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 10; pp. 3161 - 3164
• Main Authors: CHAMBERS, Laura J, STEVENS, Alexander J, THEOBALD, Pam J, BESWICK, Paul J, GLEAVE, Robert J, ROMAN, Shilina A, SENGER, Stefan, MOSES, Andrew P, MICHEL, Anton D, WALTER, Daryl S, DAVIES, David J, LIVERMORE, David G, FONFRIA, Elena, DEMONT, Emmanuel H, VIMAL, Mythily
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.05.2010
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacokinetics; Administration, Oral; Animals; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacokinetics; Biological and medical sciences; High-Throughput Screening Assays; Humans; Injections, Intravenous; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Purinergic P2 Receptor Antagonists; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Rats; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2X7; Structure-Activity Relationship; Human; Five membered ring; Intravenous administration; Rat; Nitrogen heterocycle; Rodentia; Benzene derivatives; Oral administration; P2X7 purinergic receptor; In vitro; In vivo; Vertebrata; Mammalia; Structure activity relation; Chlorine Organic compounds; Animal; Affinity; Carboxamide; Fluorine Organic compounds; Antagonist; Pharmacokinetics; Chemical synthesis; P2X7 antagonist; Lead optimisation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.096

High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.