3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 9. The synthesis and biological evaluation of novel simvastatin analogs

• Published in: Journal of medicinal chemistry 1992-10, Vol.35 (21), p.3813-3821
• Main Authors: Hartman, George D, Halczenko, Wasyl, Duggan, Mark E, Imagire, Jill S, Smith, Robert L, Pitzenberger, Steven M, Fitzpatrick, Susan L, Alberts, Alfred W, Bostedor, Rick
• Format: Article
• Language: English
• Subjects: Administration, Oral; analogs; Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Chemistry; Chemistry, Medicinal; Disease Models, Animal; Dogs; evaluation; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; hydroxymethylglutaryl-CoA reductase; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia - drug therapy; inhibitors; Life Sciences & Biomedicine; Lovastatin - analogs & derivatives; Lovastatin - chemical synthesis; Lovastatin - pharmacology; Lovastatin - therapeutic use; Magnetic Resonance Spectroscopy; Organic chemistry; Pharmacology & Pharmacy; Preparations and properties; Rats; Science & Technology; Simvastatin; Structure-Activity Relationship; synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00099a009

Substitution of hydroxy and hydroxyalkyl functionality at C-7 of the hexahydronaphthalene nucleus of simvastatin has provided novel analogs. The synthetic strategy employed epoxidation or Lewis acid-catalyzed aldol reaction of the 8-keto silyl enol ether as a key reactive intermediate. These analogs were evaluated as potential hypocholesterolemic agents via initial determination of their ability to inhibit HMG-CoA reductase in vitro. Oral activity of these compounds was determined in an acute rat model and a three-week study in cholestyramine-primed dogs. Compounds were identified that possessed in vitro and in vivo activity comparable to that of simvastatin.