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Updated: Oct 30, 2025

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Development of AC265347-Inspired Calcium-Sensing Receptor Ago-Positive Allosteric Modulators

Le Vi Dinh1,2, Aaron DeBono2, Andrew N Keller2

  • 1Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University), 381 Royal Parade, Monash University, Parkville, VIC 3052, Australia.

Chemmedchem
|July 3, 2021
PubMed

Insights

Researchers optimized a novel calcium-sensing receptor (CaSR) agonist, AC265347, to improve hyperparathyroidism treatments. This study discovered new CaSR modulators with better drug properties and reduced side effects compared to existing therapies.

Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Endocrinology

Background:

  • The calcium-sensing receptor (CaSR) is a key therapeutic target for hyperparathyroidism.
  • Current CaSR modulators like cinacalcet have limitations including adverse effects and variable efficacy.

Purpose of the Study:

  • To optimize the CaSR agonist AC265347 through structure-activity relationship (SAR) studies.
  • To discover novel CaSR modulators with improved drug-like properties and reduced side effects.

Main Methods:

  • Structure-activity relationship (SAR) analysis of AC265347.
  • Pharmacological evaluation of novel CaSR modulators in preclinical models.

Main Results:

  • AC265347 demonstrated potent suppression of parathyroid hormone (PTH) release in rats.
  • AC265347 showed a reduced propensity for hypocalcaemia compared to cinacalcet.
  • Discovery of novel AC265347-like compounds with diverse pharmacology and enhanced physicochemical properties.

Conclusions:

  • Optimized CaSR modulators, derived from AC265347, hold promise for improved hyperparathyroidism treatment.
  • These novel compounds may offer a better therapeutic window and reduced adverse effects compared to existing CaSR drugs.
Keywords:
AC265347calcium-sensing receptorclass C GPCRpositive allosteric modulatorsstructure-activity relationship

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