CHED 1313 |
| Cardiovascular disease is America's number one killer. The search for possible lipid lowering agents is of interest, since high lipid levels can lead to cardiovascular disease. The number one selling drug last year was the cholesterol lowering drug LipitorŪ with $12.7 billion in annual sales. LipitorŪ (atorvastatin) is a polysubstituted pyrrole-containing hypolipidemic agent. Herein, collections of trisubstituted pyrroles were prepared by a six-step synthesis, using solution-phase methodologies. Their structures are similar to the structure of LipitorŪ (atoravastatin). Reactions include Claisen type condensations, [2 + 3] dipolar cycloadditions and alkylations. These trisubstituted pyrroles were alkylated or acylated using sodium hydride or PS-TBD, a guanidino-labeled resin and the corresponding alkyl halide or acyl halide. A selection of these pyrrole derivatives were tested for their lipid-lowering properties which proved to be potent hypolipidemic agents in CF-1 male mice after 14 days of IP administration. These N-substituted pyrroles expand the lipid-lowering structure-activity relationships (SAR) for the hypolipidemic effects in mice of previous work with the 2,3,4-trisubstituted pyrroles (Molecules 2004, 9, 135-157). Our previous results with trisubstituted pyrroles have shown a significant decrease in cholesterol and triglyceride serum levels in CF-1 male mice, comparable to clinically used drugs. Selected compounds illustrated a lowering effect of 56% serum cholesterol this effect is better than the effects of LipitorŪ (atoravastatin). Other results for selected compounds include a 36% reduction in serum triglyceride levels. New N-substituted pyrroles have been synthesized, which have similar structures to those previously studied compounds with successful results. Herein we show the results of the synthesis and lipid-lowering effects of N-substituted pyrroles in vivo in CF-1 male mice. The synthesis of more new N-substituted pyrroles continues and their hypolipidemic effects will also be reported. |
|
Undergraduate Research Poster Session: Medicinal
2:00 PM-4:00 PM, Monday, March 26, 2007 Hyatt Regency Chicago -- Riverside Center, Poster
Division of Chemical Education |