| [ Summary ] |
It has been over thirty years since the existence of a calcium (Ca) receptor (CaR/calcium-sensing receptor; CaSR) on parathyroid cells was proposed. This receptor, shown by molecular cloning to be a G protein-coupled receptor in 1993, enables certain cells in the body to detect and respond to small changes in the concentration of extracellular Ca. The CaR is the essential protein regulating systemic Ca homeostasis. Because of this, it is a key drug target for disorders associated with hyper- or hypocalcemia. Calcimimetic drugs, which activate the CaR and inhibit parathyroid hormone (PTH) secretion, have proven useful in treating certain forms of primary and secondary hyperparathyroidism (HPT). Dr. Nemeth discovered the first drug-like calcimimetics by testing Ca channel blockers on parathyroid cells prior to the cloning of the CaR. Compounds such as fendiline and prenylamine proved to be positive allosteric modulators of the CaR and structural modifications to these compounds led to the first clinically tested calcimimetic, tecalcet (NPS R-568). Although tecalcet was safe and effective in patients with primary or secondary HPT, it had low oral bioavailability. An analog of tecalcet, cinacalcet had improved drug metabolism profiles and was the first calcimimetic to receive worldwide regulatory approval. Since then two other calcimimetics have been approved in Japan: etelcalcetide and evocalcet. |