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

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,...

Full description

Saved in:
Bibliographic Details
Published in:ChemMedChem 2021-11, Vol.16 (22), p.3451-3462
Main Authors: Dinh, Le Vi, DeBono, Aaron, Keller, Andrew N., Josephs, Tracy M., Gregory, Karen J., Leach, Katie, Capuano, Ben
Format: Article
Language:English
Subjects:
AC265347
Allosteric properties
Allosteric Regulation - drug effects
Animals
Calcium
calcium-sensing receptor
Calcium-sensing receptors
class C GPCR
Drug delivery
Humans
Hyperparathyroidism
Hypocalcemia
Models, Molecular
Modulators
Molecular Structure
Nausea
Parathyroid
Parathyroid hormone
Pharmacology
positive allosteric modulators
Rats
Receptors
Receptors, Calcium-Sensing - agonists
Side effects
Structure-Activity Relationship
Vomiting
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Positive cooperativity: The CaSR is a clinical target in the treatment of hyperparathyroidism and related diseases. AC265347 is an ago‐PAM chemically distinct from clinically approved CaSR PAMs. AC265347 potently suppressed PTH release in rats and is virtually devoid of hypocalcaemia and may therefore offer unique clinical benefits. Herein we report an SAR study disclosing AC265347‐like compounds with diverse pharmacology and improved physicochemical characteristics.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.202100368