2. Academic Validation
  3. Identification of 4-amino-2-Pyridones as new potent PCSK9 inhibitors: From phenotypic hit discovery to in vivo tolerability

Identification of 4-amino-2-Pyridones as new potent PCSK9 inhibitors: From phenotypic hit discovery to in vivo tolerability

  • Eur J Med Chem. 2023 Dec 20:265:116063. doi: 10.1016/j.ejmech.2023.116063.
Lisa Giannessi 1,  Maria Giovanna Lupo 2,  Ilaria Rossi 3,  Maria Grazia Martina 1,  Antonietta Vilella 4,  Martina Bodria 4,  Daniela Giuliani 4,  Francesca Zimetti 1,  Ilaria Zanotti 1,  Francesco Potì 5,  Franco Bernini 1,  Nicola Ferri 6,  Marco Radi 7
Affiliations

Affiliations

  • 1 Dipartimento di Scienze Degli Alimenti e Del Farmaco (DipALIFAR), Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy.
  • 2 Department of Medicine, University of Padova, 35128, Padova, Italy.
  • 3 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 351131, Padova, Italy.
  • 4 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125, Modena, Italy.
  • 5 Department of Medicine and Surgery, Unit of Neuroscience, University of Parma, 43125, Parma, Italy.
  • 6 Department of Medicine, University of Padova, 35128, Padova, Italy; Veneto Institute of Molecular Medicine, Padua, 35129, Italy. Electronic address: nicola.ferri@unipd.it.
  • 7 Dipartimento di Scienze Degli Alimenti e Del Farmaco (DipALIFAR), Università Degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy. Electronic address: marco.radi@unipr.it.
PMID: 38160616 DOI: 10.1016/j.ejmech.2023.116063
Abstract

Among the strategies to overcome the underperformance of statins in cardiovascular diseases (CVDs), the development of drugs targeting the Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is considered one of the most promising. However, only anti-PCSK9 biological drugs have been approved to date, and orally available small-molecules for the treatment of hypercholesterolemic conditions are still missing on the market. In the present work, we describe the application of a phenotypic approach to the identification and optimization of 4-amino-2-pyridone derivatives as a new chemotype with anti-PCSK9 activity. Starting from an in-house collection of compounds, functional assays on HepG2 cells followed by a chemistry-driven hit optimization campaign, led to the potent anti-PCSK9 candidate 5c. This compound, at 5 μM, totally blocked PCSK9 secretion from HepG2 cells, significantly increased LDL receptor (LDLR) expression, and acted cooperatively with simvastatin by reducing its induction of PCSK9 expression. Finally, compound 5c also proved to be well tolerated in C57BL/6J mice at the tested concentration (40 mg/kg) with no sign of toxicity or behavior modifications.

Keywords

PCSK9; Phenotypic drug discovery; Pyridones; Small molecules.

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