Next-Generation Analogues of AC265347 as Positive Allosteric Modulators of the Calcium-Sensing Receptor: Pharmacological Investigation of Structural Modifications at the Stereogenic Centre
Year: 2025
Type: article
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.
DOI: 10.3390/ijms26062580
Institutions: Monash University, Australian Research Council
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
Funder: Australian Research Council
OpenAlex ID: W4408413295