The identification of a potent, water soluble inhibitor of lipoprotein-associated phospholipase A2

• Published in: Bioorganic & medicinal chemistry letters Vol. 11; no. 5; pp. 701 - 704
• Main Authors: BOYD, Helen F, HAMMOND, Beverley, STANSFIELD, Ian G, THEOBALD, Colin J, WHITTAKER, Caroline M, HICKEY, Deirdre M. B, IFE, Robert J, LEACH, Colin A, LEWIS, V. Ann, MACPHEE, Colin H, MILLINER, Kevin J, PINTO, Ivan L, SMITH, Stephen A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 12-03-2001
• Subjects: Animals; Arteriosclerosis - drug therapy; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Drug Administration Routes; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Humans; Male; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phospholipases A - antagonists & inhibitors; Phospholipases A - metabolism; Phospholipases A2; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacology; Rabbits; Rats; Solubility; Water - chemistry; Intravenous administration; Rat; Central nervous system; Esterases; Absorption; Structure activity relation; Carboxylic acid; Chemical synthesis; Enzyme; Rodentia; Enzyme inhibitor; In vitro; Phospholipase A; Carboxylic ester hydrolases; Water soluble compound; In vivo; Vertebrata; Mammalia; Penetration; Animal; Hydrolases; Carboxamide; Pyrimidine derivatives; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00038-5

Modification of the pyrimidone 5-substituent in a series of 1-((amidolinked)-alkyl)-pyrimidones, lipophilic inhibitors of lipoprotein-associated phospholipase A2, has given inhibitors of nanomolar potency and improved physicochemical properties. Compound 23 was identified as a potent, highly water soluble. CNS penetrant inhibitor suitable for intravenous administration.