Calcimimetic Compounds: a Direct Approach to Controlling Plasma Levels of Parathyroid Hormone in Hyperparathyroidism

The Ca2+ receptor is the primary mechanism regulating the secretion of parathyroid hormone (PTH). Ligands that activate this receptor (calcimimetics) represent a novel means of lowering plasma levels of PTH. Two mechanistically distinct classes of calcimimetics that inhibit PTH secretion have been identified: type I calcimimetics are full agonists of the Ca2+ receptor and include Ca2+ and other polyvalent inorganic and organic cations; whereas type II calcimimetics, typified by phenylalkylamine compounds, behave like positive allosteric activators and increase, in a stereoselective manner, the sensitivity of the Ca2+ receptor to activation by extracellular Ca2+. The phenylalkylamine calcimimetics are orally active and decrease the plasma levels of PTH and Ca2+ in patients with primary hyperparathyroidism (HPT), a disease that so far has resisted pharmacological intervention. Such compounds are similarly safe and effective in reducing PTH levels and preventing parathyroid cell hyperplasia in rats with HPT secondary to chronic renal insufficiency and they lower plasma levels of PTH in dialysis patients with secondary HPT. Calcimimetic compounds may provide a novel therapy for treating both primary and secondary HPT.