Hypercalcemia cinacalcet

Cinacalcet is a calcimimetic agent that modulates the response of the calciumsensing receptor on the parathyroid gland, and thus may lead to a reduction in the levels of calcium. It is marketed to treat hypercalcemia (Figure 8.83). 

This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phosphate and bisphosphonates have been tried but cannot be recommended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondary hyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious, medical management of this disease will need to be reconsidered. 

The potential application of this catalytic system in industry lies in the synthesis of (R) a (1 naphthyl)ethylamine (50), a key precursor to Cinacalcet hydrochloride (51) for the treatment of hyperparathyroidism and hypercalcemia, via the hydrogenation of a (1 naphthyl)enamide at a decreased catalyst loading (0.1 mol%) in TFE under 80 bar of H2 within 24h (Scheme 9.12) [53]. 

Cinacalcet is a calcimimetic agent that lowers parathyroid hormone (PTH) levels by increasing sensing receptor to extracellular calcium. This drug is indicated in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and hypercalcemia in patients with parathyroid carcinoma. 

Calcimimetics mimic the action of calcium via the CaSR to inhibit PTH secretion by the parathyroid glands. Because of this enhanced sensitivity, they decrease PTH secretion for any given level of Ca. The calcimimetic cinacalcet (sensipar) is FDA-approved for the treatment of secondary hyperparathyroidism due to chronic renal disease and for patients with hypercalcemia associated with parathyroid carcinoma (Figure 61-9). In clinical trials, cinacalcet also effectively reduced PTH levels in patients with primary hyperparathyroidism and normalized serum calcium without altering bone mineral density for up to 2 years. 

In six cases of hthium-associated hyperparathyroidism, four had parathyroid adenomas [67, 68 ]. The authors suggested that lithium can help uncover pre-existing parathyroid disease, although there does appear to be an increased incidence of multiglandular or multiadenomatous disease in patients taking lithium. Surgical treatment is often curative when adenomas are discovered. When hypercalcemia persists, cinacalcet, a calcimimetic can be used effectively. 

Cinacalcet (85) is an oraUy active drug that decreases the secretion of the parathyroid hormone, and for this reason, it is indicated for the treatment of hypercalcemia. For its total synthesis, we started with the alkylatimi of the... 

---