Abstract 15053: New Insights into the Development of the Protease Proprotein Convertase Subtilisin-Like Kexin Type 9 Antagonists
Protease proprotein convertase subtilisin-like kexin type 9 (PCSK9) is an important target for the treatment of hypercholesterolemia. PCSK9 is synthesized as a zymogen that undergoes autocatalytic processing and secretion. Secreted PCSK9 binds to the LDL-receptor (LDLR) and chaperones it to the degradation pathway. Several pharmaceutical companies have developed injectable mAb PCSK9 antagonists. Instead, we have been developing small molecule, orally bioavailable PCSK9 antagonists. To that end, we have utilized a virtual screen approach coupled with cell-based assays to identify small molecule hits against the PCSK9 surface where the LDLR-EGF-A domain binds. The current study focuses on further developments of a new class of antagonists and their role in the regulation of lipoprotein metabolism. A structural activity relationship (SAR) study of over 250 analogues was conducted around our hit molecules and tested for their ability to inhibit the PCSK9/LDLR interactions. The most potent compounds exhibited a concentration-dependent inhibition of the PCSK9/LDLR interaction with IC50’s in the nanomolar range, an increase in the level of LDLR at an inhibitor concentration of 1.6 μM in recombinant cell-based assays, and a significant increase in the fluorescently labeled DiI-LDL uptake in the nanomolar range in situ. Our lead molecule exhibited no effect on the synthesis, processing, and secretion of PCSK9 either in the cells or into the media. In vivo pharmacological evaluation revealed that subcutaneous injection of 3 mg/kg of this antagonist resulted in a 25% reduction in LDL-C levels in mice fed a high fat/high cholesterol diet. Moreover, administration of 5 mg/kg of the inflammatory mediator lipopolysaccharide (LPS) resulted in an upregulation of the PCSK9 level associated with a 2-fold increase in LDL-C. This increase was diminished by concomitant administration of the PCSK9 inhibitor (3 mg/kg) in mice fed a high fat/high cholesterol diet. Together, the above data confirm that the reduction in LDL-C by our compound in mice is due to the effect of our compound in antagonizing the PCSK9 function. Thus, the identification of small molecule orally bioavailable antagonist against PCSK9 could lead to a new class of therapies to treat hypercholesterolemia
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