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

Le Vi Dinh, Aaron DeBono, Andrew N. Keller, Tracy M. Josephs, Karen J. Gregory, Katie Leach, Ben Capuano

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

The calcium-sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR-targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago-PAM), AC265347, is chemically distinct from clinically-approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347-like compounds with diverse pharmacology and improved physicochemical and drug-like properties.

Original languageEnglish
Pages (from-to)3451-3462
Number of pages12
JournalChemMedChem
Volume16
Issue number22
DOIs
Publication statusPublished - 19 Nov 2021

Keywords

  • AC265347
  • calcium-sensing receptor
  • class C GPCR
  • positive allosteric modulators
  • structure-activity relationship

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