Circulating levels of
calcium ion (Ca2+) are maintained within a narrow physiological range mainly by the action of
parathyroid hormone (PTH) secreted from parathyroid gland (PTG) cells. PTG cells can sense small fluctuations in plasma Ca2+ levels by virtue of a cell surface Ca2+ receptor (CaR) that belongs to the superfamily of
G protein-coupled receptors (GPCR). Compounds that activate the CaR and inhibit PTH secretion are termed 'calcimimetics' because they mimic or potentiate the effects of extracellular Ca2+ on PTG cell function. Preclinical studies with
NPS R-568, a first generation calcimimetic compound that acts as a positive allosteric modulator of the CaR, have demonstrated that
oral administration decreases serum levels of PTH and
calcium, with a leftward shift in the set-point for
calcium-regulated PTH secretion in normal rats.
NPS R-568 also suppresses the elevation of serum PTH levels and PTG
hyperplasia and can improve bone mineral density (BMD) and strength in rats with
chronic renal insufficiency (CRI). Clinical trials with
cinacalcet hydrochloride (
cinacalcet), a compound with an improved metabolic profile, have shown that long-term treatment continues to suppress the elevation of serum levels of
calcium and PTH in patients with
primary hyperparathyroidism (1HPT). Furthermore, clinical trials in patients with uncontrolled
secondary hyperparathyroidism (2HPT) have demonstrated that
cinacalcet not only lowers serum PTH levels, but also the serum
phosphorus and
calcium x
phosphorus product; these are a hallmark of an increased risk of
cardiovascular disease and mortality in dialysis patients with
end-stage renal disease. Indeed,
cinacalcet has already been approved for marketing in several countries. Calcimimetic compounds like
cinacalcet have great potential as an innovative medical approach to manage 1HPT and 2HPT.