# Next-Generation Analogues of AC265347 as Positive Allosteric Modulators of the Calcium-Sensing Receptor: Pharmacological Investigation of Structural Modifications at the Stereogenic Centre

## TL;DR

Scientists designed new drug-like compounds that interact with a receptor involved in calcium regulation, which could lead to better treatments for related diseases.

## Contribution

The study introduces next-generation analogues of AC265347 with structural modifications at the stereogenic center, revealing distinct pharmacological profiles.

## Key findings

- Compounds with alcohol functional groups showed ago-PAM profiles similar to AC265347.
- Compounds without alcohol groups acted as pure PAMs with no agonism.
- The findings suggest a way to tailor PAM activity based on structural changes.

## Abstract

The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR ago-positive allosteric modulator (PAM), AC265347 (1), exhibits a chemically and pharmacologically unique profile compared to current approved CaSR PAM therapeutics. Herein, we report a series of ‘next-generation’ analogues of AC265347, investigating the impact of structural modifications at the stereogenic centre on CaSR PAM activity. Compounds 5 and 7b featuring the alcohol functional group showed ago-PAM profiles comparable to 1, whilst compounds 6, 7 and 9 devoid of this functionality were ‘pure’ PAMs with no intrinsic agonism. These novel chemical tools provide an opportunity to explore the therapeutic potential of AC265347-like PAMs as a function of affinity, cooperativity and intrinsic agonism.