Novel calcium-sensing receptor negative allosteric modulators for the treatment of osteoporosis
The calcium-sensing receptor (CaSR) is a Class C G protein coupled receptor (GPCR). Its primary role is to negatively regulate parathyroid hormone release in response to subtle increases in extracellular calcium (Ca2+o) concentrations. Allosteric modulation of the CaSR is an important therapeutic strategy in the treatment of hyperparathyroidism and is a putative approach to treating osteoporosis and calcium handling disorders. However, CaSR drug development has been hindered by an underappreciation of key pharmacological properties that govern allosteric modulation:
1. modulator affinity for the receptor;
2. the magnitude to which modulators alter CaSR responsiveness to Ca2+o (known as cooperativity);
3. the ability of modulators to directly activate (or inhibit) CaSR signalling (known as efficacy); and
4. the capacity of the modulator to deferentially activate or modulate distinct signalling pathways to the exclusion of others (called biased agonism or biased modulation).
The current project therefore seeks to:
1. undertake a medicinal chemistry approach on a truncated structural variant of the clinical candidate ATF936, to generate a library of novel 'drug-like' CaSR modulators for a detailed SAR analysis (Scheme 1);
2. characterise the library of novel CaSR modulators using cell based assays and analytical pharmacology to evaluate SAR effects on CaSR modulator affinity, cooperativity, efficacy and bias.