NPS R-568 is a Ca2+ receptor agonist ("calcimimetic") compound that reduces circulating parathyroid hormone (PTH) levels in rats and humans with mild secondary hyperparathyroidism (secondary HPT) resulting from chronic renal insufficiency (CRI). These studies extend those observations to show that NPS R-568 is equally effective in decreasing plasma PTH and Ca2+ levels in rats with mild or severe secondary HPT, resulting either from CRI or from dietary calcium deficiency. Male rats were 5/6 nephrectomized and fed either normal chow or a high-phosphorus diet; other normal rats were fed a low-calcium diet. When secondary HPT had developed, NPS R-568 was administered and blood samples were collected for up to 6 h. PTH levels decreased to a minimum level within 30 min in both CRI and calcium deficiency models of secondary HPT. PTH and Ca2+ levels remained significantly depressed for >3 h after dosing. The percentage decrease in PTH levels was unaffected by the severity of secondary HPT or the basal plasma Ca2+ or phosphate levels. In rats with severe secondary HPT, the minimum plasma PTH level after NPS R-568 was greater than the basal level in mild secondary HPT. Thus, NPS R-568 is equally effective in suppressing plasma PTH and Ca2+ levels in rats with mild or severe renal or nutritional secondary HPT.
Fused pyrimidine derivatives R 0515 3H-Quinazolin-4-ones as a New Calcilytic Template for the Potential Treatment of Osteoporosis. -Starting from a high throughput hit various kinds of compounds such as (III), (V) and (VII) are synthesized. The latter shows 50-fold potency increase compared to the parent compound. Injection of (VII) induced a rapid but transient dose-related increase in plasma parathyroid hormone levels. -(SHCHERBAKOVA*, I.; BALANDRIN, M. F.; FOX, J.; GHATAK, A.; HEATON, W. L.; CONKLIN, R. L.; Bioorg. Med. Chem. Lett. 15 (2005) 6, 1557-1560; NPS Pharm., Inc., Univ. Utah Res. Park, Salt Lake City, UT 84108, USA; Eng.) -K. Schneider 29-164
Current rat calcitonin immunoassays use human calcitonin antisera, and suffer from poor sensitivity, long incubation periods, nonspecific interferences, and unreliability. The homologous immunoradiometric assay (IRMA) for rat calcitonin described here overcomes these problems. Overnight incubation yields a detection limit of 0.4 pg/mL, a standard curve that is linear to >1800 pg/mL, and intra- and interassay coefficients of variation of <7%. Gel filtration chromatography of rat plasma and rat medullary thyroid carcinoma 44-2 cell media showed that the vast majority of immunoreactivity coeluted with calcitonin standard. In 44-2 cells, increasing extracellular Ca2+ concentration or incubation with the calcimimetic compound NPS R-467 markedly increased calcitonin secretion. Plasma calcitonin levels were elevated in rats anesthetized with ketamine/xylazine and in conscious rats with chronic renal insufficiency. Calcitonin levels decreased following EGTA-induced hypocalcemia and were undetectable after thyroparathyroidectomy. In normal conscious rats, plasma calcitonin levels averaged 3-5 pg/mL and increased up to 100-fold following calcium (Ca) infusion or NPS R-467 administration. The assay also quantified calcitonin in plasma of normal and Ca-injected mice. This assay has revealed that plasma calcitonin levels in normal rats are much lower than the detection limits of most existing assays, but can increase by 100-fold on activation of the C-cell Ca2+ receptor.
Fused pyrimidine derivatives R 0515 Design, New Synthesis, and Calcilytic Activity of Substituted 3H-Pyrimidin-4-ones. -Compound (IXc) is reported to show the strongest calcium receptor antagonistic activity of all tested compounds. -(SHCHERBAKOVA*, I.; HUANG, G.; GEOFFROY, O. J.; NAIR, S. K.; SWIERCZEK, K.; BALANDRIN, M. F.; FOX, J.; HEATON, W. L.; CONKLIN, R. L.; Bioorg. Med. Chem. Lett. 15 (2005) 10, 2537-2540; Drug Discovery, NPS Pharm., Inc., Salt Lake City, UT 84108, USA; Eng.) -C. Oppel 38-164
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