Development of Oral Small Molecule PCSK9 Antagonist

项目总结/文摘:

Project Summary/Abstract: The epidemic of cardiovascular disease (CVD) is a global phenomenon that remains the number one cause of death throughout the world, killing nearly 17.3 million people per year; a number that is expected to grow to 23.6 million by 2030. A high cholesterol level is well-known risk factors for heart disease. Although blood cholesterol can be lowered using a number of marketed drugs, of which statins are the leading drugs, only 38% of patients taking these drugs are achieving the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program (NCEP). Furthermore, patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapy, and are at very high risk of premature cardiovascular disease. These and other patients will dramatically benefit from an aggressive treatment of hypercholesterolemia. The long-term goal of this work is to develop novel orally bioavailable drugs for cholesterol lowering. Our therapeutic target is the protease proprotein convertase subtilisin-like kexin type 9 (PCSK9). PCSK9 controls the degradation of the LDL receptor (LDLR) in the liver and thereby contributes to cholesterol homeostasis. PCSK9 is synthesized as a precursor protein that undergoes processing. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. To achieve our goal, we identified nanomolar orally active small molecule PCSK9/LDLR antagonists and demonstrated its efficacy in animal model. As part of this Phase-II proposal, we will undertake all the work required to characterize these compounds in multiple animal models for the proof of concept and conduct safety assessment in order to advance the lead compound toward IND-enabling studies and clinical trials.