Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.

摘要: The inhibition of microsomal triglyceride transfer protein (MTP) blocks the hepatic secretion very low density lipoproteins (VLDL) and intestinal chylomicrons. Consequently, this mechanism provides a highly efficacious pharmacological target for lowering lipoprotein (LDL) cholesterol reduction postprandial lipemia. combination these effects could afford unprecedented benefit in treatment atherosclerosis consequent cardiovascular disease. promise therapeutic has attracted widespread interest pharmaceutical industry. Independent efforts have yielded strikingly similar series lipophilic amide inhibitors. way which evolutionary paths distinct inhibitor tended to converge through course robotics-assisted synthesis is illustrated with candidates from Bristol-Myers Squibb Pfizer. Hanging balance exceptional potency compounds presented are potential adverse due blockage fat absorption lipid secretion. Finding degree efficacy that can be safely tolerated defines dilemma surrounding advancement clinical practice.