Discovery of Novel and Potent Orally Active Calcium-Sensing Receptor Antagonists that Stimulate Pulselike Parathyroid Hormone Secretion: Synthesis and Structure−Activity Relationships of Tetrahydropyrazolopyrimidine Derivatives

2011 ◽  
Vol 54 (5) ◽  
pp. 1430-1440 ◽  
Author(s):  
Masato Yoshida ◽  
Akira Mori ◽  
Etsuo Kotani ◽  
Masahiro Oka ◽  
Haruhiko Makino ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Receptor Antagonists ◽  
Structure Activity Relationships ◽  
Calcium Sensing ◽  
Structure Activity ◽  
Active Calcium ◽  
Orally Active

Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

2009 ◽  
Vol 19 (16) ◽  
pp. 4555-4559 ◽  
Author(s):  
Mary T. Didiuk ◽  
David A. Griffith ◽  
John W. Benbow ◽  
Kevin K.C. Liu ◽  
Daniel P. Walker ◽  
...  
Keyword(s):  
Calcium Sensing Receptor ◽  
Receptor Antagonists ◽  
Short Acting ◽  
Calcium Sensing ◽  
Active Calcium ◽  
Orally Active

scholarly journals Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism

2005 ◽  
Vol 153 (4) ◽  
pp. 587-594 ◽  
Author(s):  
Takehisa Kawata ◽  
Yasuo Imanishi ◽  
Keisuke Kobayashi ◽  
Takao Kenko ◽  
Michihito Wada ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Primary Hyperparathyroidism ◽  
Secondary Hyperparathyroidism ◽  
Murine Model ◽  
Hormone Secretion ◽  
Suppressive Effect ◽  
Receptor Expression ◽  
Parathyroid Glands ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet’s effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and CaR expression on the parathyroid glands requires better understanding. To investigate its suppressive effect on PTH secretion in primary hyperparathyroidism, in which hypercalcemia may already have stimulated considerable CaR activity, we investigated the effect of cinacalcet HCl on PTH-cyclin D1 transgenic mice (PC2 mice), a model of primary hyperparathyroidism with hypo-expression of CaR on their parathyroid glands. A single administration of 30 mg/kg body weight (BW) of cinacalcet HCl significantly suppressed serum calcium (Ca) levels 2 h after administration in 65- to 85-week-old PC2 mice with chronic biochemical hyperparathyroidism. The percentage reduction in serum PTH was significantly correlated with CaR hypo-expression in the parathyroid glands. In older PC2 mice (93–99 weeks old) with advanced hyperparathyroidism, serum Ca and PTH levels were not suppressed by 30 mg cinacalcet HCl/kg. However, serum Ca and PTH levels were significantly suppressed by 100 mg/kg of cinacalcet HCl, suggesting that higher doses of this compound could overcome severe hyperparathyroidism. To conclude, cinacalcet HCl demonstrated potency in a murine model of primary hyperparathyroidism in spite of any presumed endogenous CaR activation by hypercalcemia and hypo-expression of CaR in the parathyroid glands.

Association of Polymorphic Alleles of the Calcium-Sensing Receptor Gene with Parathyroid Hormone Secretion in Hemodialysis Patients

Nephron ◽  
2000 ◽  
Vol 85 (4) ◽  
pp. 317-323 ◽  
Author(s):  
Shozo Yano ◽  
Toshitsugu Sugimoto ◽  
Michiko Kanzawa ◽  
Tatsuo Tsukamoto ◽  
Tetsuya Hattori ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Gene ◽  
Hormone Secretion ◽  
Hemodialysis Patients ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Calcium Sensing Receptor Gene

scholarly journals A Novel Calcium-Sensing Receptor Antagonist Transiently Stimulates Parathyroid Hormone Secretion in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (4) ◽  
pp. 2015-2022 ◽  
Author(s):  
Brian J. Arey ◽  
Ramakrishna Seethala ◽  
Zhengping Ma ◽  
Aberra Fura ◽  
Jennifer Morin ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Receptor Antagonist ◽  
Hormone Secretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing
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