Dinh, Le Vi; Dangerfield, Jesse; DeBono, Aaron; Keller, Andrew N; Josephs, Tracy M; Gregory, Karen J; Leach, Katie; Capuano, Ben

DOI:

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.

Keywords

positive allosteric modulator ; PAM ; calcium-sensing receptor ; AC265347 ; stereogenic centre

Purchased from AmBeed