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Published on: November 18, 2013
An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits
J R Wetterau1, R E Gregg, T W Harrity
1Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. Wetterau_John_R@msmail.bms.com
Abstract:
Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.
Insights
Small molecule inhibitors targeting microsomal triglyceride transfer protein (MTP) can reduce atherogenic lipoproteins. Compound 9 demonstrated efficacy in preclinical models, suggesting potential for treating hyperlipidemia in humans.
Area of Science:
- Biochemistry
- Pharmacology
- Genetics
Background:
- Abetalipoproteinemia results from microsomal triglyceride transfer protein (MTP) defects, preventing apolipoprotein B-lipoprotein production.
- Atherogenic lipoproteins contribute to cardiovascular disease.
- MTP plays a crucial role in lipoprotein assembly and secretion.
Purpose of the Study:
- To investigate the therapeutic potential of MTP small molecule inhibitors.
- To develop a potent MTP inhibitor for treating conditions with high atherogenic lipoproteins.
Main Methods:
- High-throughput screening identified initial MTP inhibitors.
- Synthesis of a highly potent MTP inhibitor (compound 9) was directed.
- Compound 9 efficacy was tested in rodent models and Watanabe-heritable hyperlipidemic (WHHL) rabbits.
Main Results:
- Compound 9 effectively inhibited lipoprotein particle production in preclinical models.
- Plasma lipoprotein levels were normalized in WHHL rabbits, a model for familial hypercholesterolemia.
- The study validated MTP inhibition as a strategy for managing atherogenic lipoproteins.
Conclusions:
- Small molecule MTP inhibition is a viable therapeutic strategy.
- Compound 9 shows promise for lowering atherogenic lipoproteins in humans.
- Further development of compound 9 or its derivatives could lead to new treatments for hyperlipidemia.
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