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Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using
George Chang1, Roger B Ruggeri, H James Harwood
1Departments of Metabolic Diseases and Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. george_c_chang@groton.pfizer.com
Abstract:
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.
Insights
Inhibiting microsomal triglyceride transfer protein (MTP) effectively lowers LDL cholesterol and postprandial lipemia. However, potential adverse effects on fat absorption and lipid secretion present a clinical challenge.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Medicine
Background:
- Microsomal triglyceride transfer protein (MTP) plays a crucial role in lipoprotein assembly and secretion.
- Inhibition of MTP effectively blocks hepatic very low density lipoprotein (VLDL) and intestinal chylomicron secretion.
- This mechanism presents a promising therapeutic target for managing dyslipidemia and cardiovascular disease.
Purpose of the Study:
- To explore the development of lipophilic amide inhibitors targeting MTP.
- To illustrate the convergence of distinct inhibitor series through robotics-assisted synthesis.
- To evaluate the therapeutic potential and safety profile of MTP inhibitors.
Main Methods:
- Robotics-assisted synthesis was employed to develop and optimize MTP inhibitors.
- Independent research efforts by pharmaceutical companies (Bristol-Myers Squibb, Pfizer) yielded similar inhibitor series.
- Potency and potential adverse effects were assessed.
Main Results:
- Strikingly similar series of lipophilic amide inhibitors were independently developed.
- Robotics-assisted synthesis facilitated the convergence of distinct inhibitor evolutionary paths.
- Compounds demonstrated exceptional potency in inhibiting MTP.
Conclusions:
- MTP inhibition is a potent strategy for lowering LDL cholesterol and reducing postprandial lipemia, offering potential benefits for atherosclerosis and cardiovascular disease.
- The development of highly effective MTP inhibitors has attracted significant pharmaceutical interest.
- Balancing the potent efficacy of MTP inhibitors against potential adverse effects like impaired fat absorption and hepatic lipid secretion is critical for clinical advancement.