Abstract
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.
Footnotes
This research was wholly funded by Amgen, Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.178681.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CaSR
- calcium-sensing receptor
- hCaSR
- human CaSR
- CKD
- chronic kidney disease
- ESRD
- end-stage renal disease
- FLIPR
- fluorescent imaging plate reader
- IP
- inositol phosphate
- PTH
- parathyroid hormone
- Nx
- nephrectomized
- SHPT
- secondary hyperparathyroidism
- R-568
- 3-(2-chlorophenyl)-N-((1R)-1-(3-methoxyphenyl)ethyl)-1-propanamine
- HEK
- human embryonic kidney
- DMEM
- Dulbecco's modified Eagle's medium
- DMSO
- dimethyl sulfoxide
- HBSS
- Hanks' balanced salt solution
- BSA
- bovine serum albumin
- ELISA
- enzyme-linked immunosorbent assay
- ERK
- extracellular signal-regulated kinase.
- Received December 28, 2010.
- Accepted March 16, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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