Parathyroid hormone (PTH) secretion is regulated by a cell surface Ca 2؉ receptor that detects small changes in the level of plasma Ca 2؉ . Because this G protein-coupled receptor conceivably provides a distinct molecular target for drugs useful in treating bone and mineral-related disorders, we sought to design small organic molecules that act on the Ca 2؉ receptor. We discovered that certain phenylalkylamine compounds, typified by NPS R-568 and its deschloro derivative NPS receptor are termed calcimimetics. The discovery of calcimimetic compounds with potent and selective activity enables a pharmacological approach to regulating plasma levels of PTH. Calcimimetic compounds could conceivably provide a specific medical therapy for primary hyperparathyroidism.The concentration of ionized calcium (Ca 2ϩ ) in plasma is regulated largely by parathyroid hormone (PTH), which acts on the kidney and on bone to increase the level of plasma Ca The Ca 2ϩ receptor is a member of the G protein-coupled receptor superfamily and possesses an unusually large extracellular domain, the characteristic seven transmembrane domain, and a relatively long cytoplasmic tail. In these topological aspects, the Ca 2ϩ receptor is similar to metabotropic glutamate receptors (mGluR), although the sequence homology between these receptors is only about 25%. The human (1,078 amino acids) and bovine (1,085 amino acids) parathyroid cell Ca 2ϩ receptors are glycosylated proteins of ϳ120 kDa and are 93% identical (5). The Ca 2ϩ receptor expressed on authentic parathyroid cells or in heterologous cellular systems couples to phospholipase C and, when activated by increased concentrations of extracellular Ca 2ϩ , elicits rapid increases in inositol 1,4,5-trisphosphate and [Ca 2ϩ ] i (2, 4, 6). Thus, in its functional and structural properties, the parathyroid Ca 2ϩ receptor is akin to other cell surface receptors that initially transduce extracellular signals into functional cellular responses. The difference is that the physiological ligand for the Ca 2ϩ receptor is an inorganic ion, rather than an organic molecule.G protein-coupled receptors have been a classic site of action for drugs useful in treating various diseases. As a member of the G protein-coupled receptor superfamily, the Ca 2ϩ receptor is seemingly an ideal target for new pharmaceuticals useful in treating disorders of bone and mineral metabolism, such as hyperparathyroidism and osteoporosis. At present, however, the only ligands known to act on the Ca 2ϩ receptor are other inorganic di-and trivalent cations (2, 7) and organic polycations (8-10) that are nonselective and lack utility as systematic therapeutics. The present report describes the results of our initial efforts to devise a small organic compound that selectively acts on the parathyroid Ca 2ϩ receptor yet lacks a polycationic structure. NPS R-467 and NPS R-568 (Fig. 1) are two compounds that emerged from this effort. They are potent and selective activators of the Ca 2ϩ receptor and inhibit PTH secretion in vitro....

Calcimimetic compounds, which activate the parathyroid cell Ca 2ϩ receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca 2ϩ ([Ca 2ϩ ] i ) in human embryonic kidney 293 cells expressing the human parathyroid CaR. Cinacalcet HCl (EC 50 ϭ 51 nM) in the presence of 0.5 mM extracellular Ca 2ϩ elicited increases in [Ca 2ϩ ] i in a dose-and calcium-dependent manner. Similarly, in the presence of 0.5 mM extracellular Ca 2ϩ , cinacalcet HCl (IC 50 ϭ 28 nM) produced a concentration-dependent decrease in PTH secretion from cultured bovine parathyroid cells. Using rat medullary thyroid carcinoma 6-23 cells expressing the CaR, cinacalcet HCl (EC 50 ϭ 34 nM) produced a concentrationdependent increase in calcitonin secretion. In vivo studies in rats demonstrated cinacalcet HCl is orally bioavailable and displays approximately linear pharmacokinetics over the dose range of 1 to 36 mg/kg. Furthermore, this compound suppressed serum PTH and blood-ionized Ca 2ϩ levels and increased serum calcitonin levels in a dose-dependent manner. Cinacalcet was about 30-fold more potent at lowering serum levels of PTH than it was at increasing serum calcitonin levels. The S-enantiomer of cinacalcet (S-AMG 073) was at least 75-fold less active in these assay systems. The present findings provide compelling evidence that cinacalcet HCl is a potent and stereoselective activator of the parathyroid CaR and, as such, might be beneficial in the treatment of hyperparathyroidism.

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Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.