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

  • ChemMedChem. 2021 Nov 19;16(22):3451-3462. doi: 10.1002/cmdc.202100368.
Le Vi Dinh  1  2 ,  Aaron DeBono  2 ,  Andrew N Keller  2 ,  Tracy M Josephs  2 ,  Karen J Gregory  2  3 ,  Katie Leach  2  3 ,  Ben Capuano  1
Affiliations
  • 1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University), 381 Royal Parade, Monash University, Parkville, VIC 3052, Australia.
  • 2. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University), 381 Royal Parade, Monash University, Parkville, VIC 3052, Australia.
  • 3. Department of Pharmacology, Monash University, 9 Ancora Imparo Way, Clayton, VIC 3800, Australia.
PMID: 34216111 DOI: 10.1002/cmdc.202100368
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.

Keywords
AC265347; calcium-sensing receptor; class C GPCR; positive allosteric modulators; structure-activity relationship.
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