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 chronic kidney disease (CKD) patients on dialysis with secondary hyperparathyroidism (SHPT). A calcimimetic that displays increased separation of PTH vs. Ca2+ lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease since hypocalcaemia can develop in this population. Towards 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 compound effects upon 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 hypocalcaemia. Furthermore, our third generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells as compared to 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 hypocalcaemia since the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion.
- Received December 28, 2010.
- Revision received March 15, 2011.
- Accepted March 16, 2011.
- The American Society for Pharmacology and Experimental Therapeutics