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

The calcium-sensing receptor (CaSR) is a validated therapeutic target in the treatment of hyperparathyroidism and related diseases. The CaSR <i>ago</i>-positive allosteric modulator (PAM), AC265347 (<b>1</b>), 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 <b>5</b> and <b>7b</b> featuring the alcohol functional group showed <i>ago</i>-PAM profiles comparable to <b>1</b>, whilst compounds <b>6</b>, <b>7</b> and <b>9</b> 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.