Homan_1997_Curr.Pharma.Design_3_29

The growing evidence linking elevated plasma cholesterol levels, to increased risk of heart disease and the demonstration of a positive correelation between plasma levels of low density lipoprotein cholesterol and cholesterol absorption efficiency in humans have been a major impetus for efforts to develo cholesterol absorption inhibitors. Not only do such agents act on a major component of the total cholesterol turnover within the body, but, since they are directed at a cholesterol pool that is external to the circulation (i.e. intestinal lumen), there is potential Fot the development of efficacious compounds that function non-systemically and thereby avoid the toxicity issues associated with agents that must enter the circulation to act. The potential for such agents is already evident from the clinical experience with neomycin and beta-sitosterol which have yielded moderate success in the treatment of hypcrcholestetolemic patients. The creation of more efficacious compounds is focused on the development of inhibitors of specific enzymes considered to facilitate the cholesterol absorption process and on non-specific agents that enhance cholesterol retention within the intestinal contents by perturbing cholesterol distribution and exchange among the various lipid phases of the contents. In addition, a new method for blocking cholesterol uptake is proprosed that is based on ihe inhibition of pancreatic phospholipase A2