Functional proteins involved in regulation of intracellular Ca(2+) for drug development: the extracellular calcium receptor and an innovative medical approach to control secondary hyperparathyroidism by calcimimetics.
Circulating levels of calcium ion (Ca(2+)) are maintained within a narrow physiological range mainly by the action of parathyroid hormone (PTH) secreted from parathyroid cells. Parathyroid cells can sense small fluctuations in plasma Ca(2+) levels by virtue of a cell surface Ca(2+) receptor (CaR) that belongs to the superfamily of G-protein-coupled receptors. Calcimimetics are positive allosteric modulators that activate the CaR on parathyroid cells and thereby immediately suppress PTH secretion. Pre-clinical studies with NPS R-568, a first generation calcimimetic compound, have demonstrated that daily oral administration inhibits the elevation of plasma PTH levels and parathyroid gland hyperplasia and ameliorates impaired bone qualities in rats with chronic renal insufficiency. The results of clinical trials with cinacalcet hydrochloride, a second generation calcimimetic compound, have shown that calcimimetics possess lowering effects not only on serum PTH levels but also on serum calcium x phosphorus product levels, a hallmark of an increased risk for cardiovascular death in dialysis patients with end-stage renal disease (ESRD). Thus, calcimimetics have considerable potential as an innovative medical approach to manage secondary hyperparathyroidism associated with ESRD. Indeed, cinacalcet hydrochloride has been approved in several countries and is the first positive allosteric modulator of any G protein-coupled receptor to reach the market.
Nagano
Nobuo
N
Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd., Gunma. n-nagano@kirin.co.jp
Nemeth
Edward F
EF
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D000069449:Cinacalcet; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000150:complications; D008954:Models, Biological; D015394:Molecular Structure; D009281:Naphthalenes / Q000627:therapeutic use; D010280:Parathyroid Glands / Q000166:cytology / Q000378:metabolism; D010281:Parathyroid Hormone / Q000097:blood / Q000378:metabolism; D010627:Phenethylamines; D011437:Propylamines; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000187:drug effects* / Q000235:genetics
D000814:Aniline Compounds; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D044169:Receptors, Calcium-Sensing; D002118:Calcium; D000069449:Cinacalcet