TY - JOUR T1 - Discovery of a Calcimimetic with Differential Effects on Parathyroid Hormone and Calcitonin Secretion JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 681 LP - 691 DO - 10.1124/jpet.110.178681 VL - 337 IS - 3 AU - Charles Henley III AU - Yuhua Yang AU - James Davis AU - Jenny Ying Lin Lu AU - Sean Morony AU - Wei Fan AU - Monica Florio AU - Banghua Sun AU - Edward Shatzen AU - James K. Pretorius AU - William G. Richards AU - David J. St. Jean, Jr AU - Christopher Fotsch AU - Jeff D. Reagan Y1 - 2011/06/01 UR - http://jpet.aspetjournals.org/content/337/3/681.abstract N2 - Calcimimetics are positive allosteric modulators to the calcium-sensing receptor (CaSR). Activation of the CaSR inhibits the secretion of parathyroid hormone (PTH), stimulates the secretion of calcitonin, and decreases serum calcium (Ca2+). Cinacalcet, a second-generation calcimimetic, is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism. A calcimimetic that displays increased separation of PTH versus Ca2+ lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population. Toward this end, we developed a third-generation calcimimetic, determined the molecular pharmacological properties of it using an operation model of allosteric modulation/agonism, and measured the compound effects on PTH, serum ionized Ca2+, and calcitonin levels in 5/6 nephrectomized rats. We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia. Furthermore, our third-generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine (R-568), a first-generation calcimimetic. These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion. ER -