Synthesis and hypocholesterolemic activity of 6,7-dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-diones, novel inhibitors of acylCoA: cholesterol O-acyltransferase

• Published in: Journal of medicinal chemistry Vol. 34; no. 5; pp. 1721 - 1727
• Main Authors: Larsen, Scott D, Spilman, Charles H, Bell, Frank P, Dinh, Dac M, Martinborough, Esther, Wilson, Gracella J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-05-1991
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Chemical Phenomena; Chemistry; Cholesterol - blood; Cholesterol - metabolism; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Male; Organic chemistry; Preparations and properties; Pyrimidinones - chemical synthesis; Pyrimidinones - pharmacology; Rats; Rats, Inbred Strains; Sterol O-Acyltransferase - antagonists & inhibitors; Structure-Activity Relationship; Angular nitrogen heterocycle; Lactam; Enzyme inhibitor; Tricyclic compound; In vitro; Biological activity; Antilipemic agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00109a028

A novel series of 6,7-dihydro-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione inhibitors of the enzyme acyl-CoA:cholesterol O-acyltransferase is described. A number of these derivatives were found to be potent modulators of serum lipoprotein levels in cholesterol-fed rats. Further evaluation of one of the most effective analogues confirmed that it was significantly blocking the absorption of cholesterol from the gut.