Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.
The inhibition of microsomal triglyceride transfer protein (MTP) blocks the hepatic secretion of very low density lipoproteins (VLDL) and the intestinal secretion of chylomicrons. Consequently, this mechanism provides a highly efficacious pharmacological target for the lowering of low density lipoprotein (LDL) cholesterol and reduction of postprandial lipemia. The combination of these effects could afford unprecedented benefit in the treatment of atherosclerosis and consequent cardiovascular disease. The promise of this therapeutic target has attracted widespread interest in the pharmaceutical industry. Independent efforts have yielded strikingly similar series of lipophilic amide inhibitors. The way in which the evolutionary paths of distinct inhibitor series have tended to converge through the course of robotics-assisted synthesis efforts is illustrated with candidates from Bristol-Myers Squibb and Pfizer. Hanging in the balance with the exceptional potency of the compounds presented are the potential adverse effects due to blockage of intestinal fat absorption and hepatic lipid secretion. Finding a degree of efficacy that can be safely tolerated defines the dilemma surrounding the advancement of these compounds to clinical practice.
Chang
George
G
Departments of Metabolic Diseases and Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. george_c_chang@groton.pfizer.com
Ruggeri
Roger B
RB
Harwood
H James
HJ
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D006801:Humans; D012371:Robotics / Q000379:methods / Q000639:trends; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000639:trends
D002352:Carrier Proteins; D015243:Cholesterol, VLDL; C106092:microsomal triglyceride transfer protein