5,6-Diphenylpyridazine Derivatives as Acyl-CoA:Cholesterol Acyltransferase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 44; no. 24; pp. 4292 - 4295
• Main Authors: Giovannoni, Maria Paola, Piaz, Vittorio Dal, Kwon, Byoung-Mog, Kim, Mi-Kyung, Kim, Young-Kook, Toma, Lucio, Barlocco, Daniela, Bernini, Franco, Canavesi, Monica
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.2001; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Cell-Free System; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; General and cellular metabolism. Vitamins; In Vitro Techniques; Life Sciences & Biomedicine; Macrophages - drug effects; Macrophages - enzymology; Medical sciences; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Rats; Science & Technology; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship; POTENT; SERIES; ATHEROSCLEROSIS; ESTERIFICATION; ABSORPTION; COENZYME-A; IDENTIFICATION; ACAT INHIBITORS; ANTIATHEROSCLEROTIC AGENTS; Acyltransferases; Rat; Enzyme; Aliphatic compound; Nitrogen heterocycle; Transferases; Liver; Rodentia; Benzene derivatives; Enzyme inhibitor; Microsome; In vitro; Cholesterol; Vertebrata; Mammalia; Structure activity relation; Mouse; Six membered ring; Chemical synthesis; Antilipemic agent; Macrophage; Sterol O-acyltransferase
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010807h

Alkyl-5,6-diphenylpyridazine derivatives combining several main features of ACAT inhibitors, such as a long alkyl side chain linked to a heterocycle and the o-diphenyl system, were synthesized and tested. Moreover, modeling studies on representative terms were performed. Some compounds displayed ACAT inhibition in the micromolar range, both on the enzyme isolated from rat liver microsomes and in cell-free homogenate of murine macrophages.