nps-r-467 and Hyperparathyroidism

The common feature of both primary and secondary hyperparathyroidism despite differences in their etiopathogenesis is excess parathormone (PTH) secretion. Calcium sensing receptor (CaR) belongs to G-protein coupled receptors superfamily and plays central role in the regulation of PTH secretion. Mutations in receptor's gene lead to PTH suppression set-point shift into higher (familial benign hypocalciuric hypercalcemia) or lower Ca2+ levels (familial hypercalciuric hypocalcemia). Calcimimetics are a new class of drugs which increase the CaR response to agonist binding by allosteric conformation modification. First generation calcimimetics: NPS R-467 and NPS R-568 revealed their effectiveness in PTH suppression in experimental animal model. Short-term trials with NPS R-568 used in people with primary or secondary hyperparathyroidism confirmed significant PTH suppression. In further clinical trials a second generation calcimimetic: AMG 073 was used. AMG 073 intake was related to decrease of serum PTH and phosphorus concentrations and Ca x P product suppression with low number of hypocalcemia or other side effects. In the future calcimimetics could be an alternative to vitamin D active metabolites or analogs treatment and to surgical procedures.

Topics: Allosteric Site; Aniline Compounds; Animals; Calcium; Calcium-Binding Proteins; Cinacalcet; Humans; Hyperparathyroidism; Naphthalenes; Parathyroid Hormone; Phenethylamines; Propylamines; Receptors, Calcium-Sensing; Treatment Outcome

The cell surface calcium receptor (Ca2+ receptor) is a particularly difficult receptor to study because its primary physiological ligand, Ca2+, affects numerous biological processes both within and outside of cells. Because of this, distinguishing effects of extracellular Ca2+ mediated by the Ca2+ receptor from those mediated by other mechanisms is challenging. Certain pharmacological approaches, however, when combined with appropriate experimental designs, can be used to more confidently identify cellular responses regulated by the Ca2+ receptor and select those that might be targeted therapeutically. The Ca2+ receptor on parathyroid cells, because it is the primary mechanism regulating secretion of parathyroid hormone (PTH), is one such target. Calcimimetic compounds, which active this Ca2+ receptor and lower circulating levels of PTH, have been developed for treating hyperparathyroidism. The converse pharmaceutical approach, involving calcilytic compounds that block parathyroid cell Ca2+ receptors and stimulate PTH secretion thereby providing an anabolic therapy for osteoporosis, still awaits clinical validation. Although Ca2+ receptors are expressed throughout the body and in many tissues that are not intimately involved in systemic Ca2+ homeostasis, their physiological and/or pathological significance remains speculative and their value as therapeutic targets is unknown.

Topics: Aniline Compounds; Animals; Calcium; Calcium Channels; Cinacalcet; Fendiline; Humans; Hyperparathyroidism; Naphthalenes; Osteoporosis; Parathyroid Glands; Phenethylamines; Propylamines; Receptors, Calcium-Sensing; Stereoisomerism