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Design of Next-Generation DGAT2 Inhibitor PF-07202954 with Longer Predicted Half-Life.

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|October 18, 2023
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Summary

Researchers developed PF-07202954, a novel Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, to treat non-alcoholic steatohepatitis (NASH). This extended-half-life drug candidate effectively reduces liver triglyceride levels in preclinical models.

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Hepatology

Background:

  • Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitors are investigated for non-alcoholic steatohepatitis (NASH) treatment.
  • Lowering liver triglyceride content is a therapeutic strategy for NASH.
  • There is a need for DGAT2 inhibitors with improved pharmacokinetic profiles, such as extended half-life.

Purpose of the Study:

  • To discover and develop an extended-half-life Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor.
  • To optimize inhibitor properties for a balance of potency, clearance, and permeability.
  • To identify a clinical candidate for NASH treatment.

Main Methods:

  • Structure-based drug design incorporating a basic moiety.
  • Fine-tuning lipophilicity and basicity through electrophilic fluorine addition.
  • Preclinical evaluation of physicochemical properties, pharmacokinetics, and efficacy in a Western-diet-fed rat model.

Main Results:

  • Discovery of PF-07202954 (12), a novel, weakly basic DGAT2 inhibitor.
  • PF-07202954 exhibits a higher volume of distribution and longer half-life in preclinical species.
  • PF-07202954 successfully reduced liver triglyceride content in a preclinical NASH model.

Conclusions:

  • PF-07202954 is a promising DGAT2 inhibitor with an optimized pharmacokinetic profile for potential NASH therapy.
  • The developed molecule has advanced into clinical studies.
  • This work demonstrates a successful strategy for designing extended-half-life DGAT2 inhibitors.