Discovery and Development of an Oral, Small Molecule PCSK9/LDLR Antagonist Volume 3 - Issue 4

Nabil A. Elshourbagy¹*, Harold Meyers¹, Sherin S Abdel-Meguid¹, Kavitha Godugu², Taher A Salaheldin², Dhruba J Bharali² and Shaker A Mousa²

• ¹Shifa Biomedical Corporation, 1 Great Valley Parkway, Suite 8, Malvern, PA 19355, USA
• ²The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY 12144, USA

Received:April 28, 2021;   Published: May 5, 2021

Corresponding author: Nabil A. Elshourbagy, Shifa Biomedical Corporation, 1 Great Valley Parkway, Suite 8, Malvern, PA 19355, USA

DOI: 10.32474/ACR.2021.03.000167

 

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Abstract

PCSK9 is a well validated target for the treatment of hypercholesterolemia. Several pharmaceutical companies focused on the development of injectable monoclonal antibodies. Shifa Biomedical has focused on developing orally bioavailable small molecule PCSK9/LDLR antagonists. PCSK9 antagonists were identified through virtual screening at the PCSK9 surface where the LDLR-EGF-A binds. An SAR study of many analogues were done for their ability to antagonize the PCSK9/LDLR interaction in an in vitro ELISA assay, upregulate the LDLR in a cell-based assay, and increase LDL uptake in a fluorescent Dil-LDL assay. The most potent compound meeting these criteria was P-4, formulated by a nanocrystal/targeted delivery approach for the in vivo studies. Nano formulated P-4 was named P-21. P-4 exhibited a concentration-dependent inhibition of the PCSK9/LDLR interaction with an IC50 in the nanomolar range, an increase in the level of LDLR in recombinant cell-based assays, and a significant increase in the fluorescently labeled DiILDL uptake in the nanomolar range. P-4 also exhibited a good safety profile as demonstrated in vitro and in in vivo animal models. P-21 showed improved PK and PD of P-4. Oral administration of P-21 at 1, 3, 10, and 30 mg/kg in C57BL/6 mice fed a high-fat diet resulted in approximately a 20, 40, 60, and 90% LDL-C lowering, respectively. The identification of a small molecule orally bioavailable antagonist against PCSK9 could lead to a new class of therapies to treat hypercholesterolemia, especially for those patients that are statin resistant or stain intolerant.

Keywords: Atherosclerosis; low-density lipoprotein cholesterol; PCSK9 small molecule inhibitors; hypercholesterolemia; cholesterol

Abbreviations: AHA: American Heart Association; CETP: cholesteryl ester transfer protein; DHA: docosahexaenoic acid; DLS: dynamic light scattering; EC50: effective concentration ; EPA: eicosatetraenoic acid; ELS: electrophoretic light scattering; HPMC-AS: Hydroxypropyl methylcellulose acetate succinate; LDL-C: low-density lipoprotein-cholesterol; LDLR-EGFA-A: low-density lipoprotein receptor epidermal growth factor homology domain A; LDLR: low-density lipoprotein receptor; PCSK9: proprotein convertase subtilisin-like kexin type 9; PEG: polyethylene glycol; PLGA: poly-(lactic-co-glycolic acid) PK: pharmacokinetics; PD: pharmacodynamics ; SLN: solid lipid nanoparticle

Abstract| Introduction| Material and Methods| Statistical Analysis| Results| Discussion| References|