TTP INHIBITIORS OF LOW DENSITY LIPPROTEIN SECRETION FOR THE MANAGEMENT OF DISEASES ASSOCIATED WITH ELEVATED BLOOD LDL LEVELS

摘要

The present invention provides for the novel method for the inhibition of microsomal triglyceride transfer protein (MTP) and/or apolipoprotein B (Apo B) secretion having Formulas I-XI in lowering serum lipids and in the prevention and treatment of related disease. Regulation of the VLDL/LDL pathway as a therapeutic means to reduce hyperlipidemia is supported from studies in liver cells and in an animal model. Accordingly, the inhibition of regulation described herein is identified as a new therapeutic target for treatment of cardiovascular disease or diseases associated with cardiovascular disease such as hyperlipidemia. Treatment of cardiovascular disease and associated conditions or diseases with the novel TTP inhibitors of the invention reduces MTP protein associated lipid production without side effects that occur with other methods of MTP protein associated lipid inhibition. We describe small molecules (disubstituted tetrahydro-tetrazolo(l,5a)pyrimidine (TTP) and a method of their use to inhibit the secretion of ApoB and LDLs from liver derived cells in tissue culture and in animal models. We further describe how to use these small molecules in the management of diseases associated with elevations of circulating LDLs.