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Updated: Oct 20, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Published on: November 15, 2013

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Overcoming the Pregnane X Receptor Liability: Rational Design to Eliminate PXR-Mediated CYP Induction

Joshi M Ramanjulu1, Shawn P Williams1, Ami S Lakdawala1

  • 1GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.

ACS Medicinal Chemistry Letters
|September 17, 2021
PubMed

Insights

Researchers developed a new drug (compound 8) that targets the calcium sensing receptor (CaSR) without activating the pregnane X receptor (PXR). This advancement aims to improve drug efficacy and reduce drug-drug interactions.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Drug Discovery

Background:

  • The pregnane X receptor (PXR) controls detoxification pathways, influencing xenobiotic excretion and drug-drug interactions.
  • Pyrimidinone 1, a CaSR antagonist, strongly activates PXR, leading to reduced drug exposure and hindering further development.

Purpose of the Study:

  • To understand and eliminate PXR activation by CaSR antagonists to improve systemic drug exposure.
  • To develop orally active CaSR antagonists suitable for clinical progression.

Main Methods:

  • Medicinal chemistry campaign focused on structure-activity relationships.
  • Utilized cocrystal structures and a de novo pharmacophore model.
  • Investigated rational elimination of PXR activation.

Main Results:

  • Identified compounds devoid of PXR activation through rational design.
  • Developed compound 8, the first orally active CaSR antagonist suitable for progression.
  • Demonstrated the successful elimination of PXR activation.

Conclusions:

  • Eliminating PXR activation is crucial for enhancing systemic exposure of CaSR antagonists.
  • The developed strategies for PXR deactivation have broad applicability across diverse chemical classes.
  • Compound 8 represents a significant advancement in developing CaSR antagonists with improved pharmacokinetic profiles and reduced drug-drug interaction potential.

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