Design, New Synthesis, and Calcilytic Activity of Substituted 3H‐Pyrimidin‐4‐ones.

Shcherbakova, I. M.; Huang, Guangfei; Geoffroy, Otto J.; Nair, Satheesh K.; Świerczek, K.; Balandrin, Manuel F.; Fox, John; Heaton, William L.; Conklin, Rebecca L.

doi:10.1002/chin.200538164

Cited by 4 publications

(6 citation statements)

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“…Figure 6 summarizes some compounds where in vivo effects on PTH have been reported. NPS Pharmaceuticals published on a series of calcilytics that contained either a quinazolinone (31) 97 or pyrimidinone (32) 98 core, functionality that is not present on 27. Representative examples from this new series of compounds were shown to elevate PTH levels in normal rats for only 5-10 min (31, 10 μmol/kg iv, PTH C max ≈ 400 pg/mL; 32, 3 μmol/kg iv, PTH C max ≈ 600 pg/mL).…”

Section: Parathyroid Hormone Receptor (Pth1r)mentioning

confidence: 99%

Emerging Targets in Osteoporosis Disease Modification

2010

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Section: Parathyroid Hormone Receptor (Pth1r)mentioning

confidence: 99%

Emerging Targets in Osteoporosis Disease Modification

2010

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“…Small molecule antagonists of the CaR, known as calcilytics or negative allosteric modulators, mimic low extracellular Ca 2+ and stimulate PTH secretion. [8][9][10][11][12][13][14][15][16][17][18] An important aspect of the pharmacology of PTH and its agonist fragments is the temporal nature of the exposure to these agents. Depending on the pattern of exposure PTH may act either as an anabolic agent, thereby building new bone, or as a catabolic agent, resulting in the loss of bone.…”

Section: Cinacalcet N-[(1r)-1-(1-naphthalenyl)ethyl]-3-[3-(trifluorom...mentioning

confidence: 99%

“…In contrast to the inhibitory effects of high Ca 2+ levels or calcimimetics on PTH secretion, low circulating Ca 2+ levels stimulate PTH secretion. Small molecule antagonists of the CaR, known as calcilytics or negative allosteric modulators, mimic low extracellular Ca 2+ and stimulate PTH secretion. − …”

Section: Introductionmentioning

confidence: 99%

Antagonists of the Calcium Receptor I. Amino Alcohol-Based Parathyroid Hormone Secretagogues

et al. 2009

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Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.

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“…Calcimimetic compounds validate the view that circulating levels of PTH can be pharmacologically controlled by a small molecule acting at the parathyroid gland CaR. On the other hand, small molecule antagonists of the CaR, known as calcilytics, serve to mimic a hypocalcemic state and elicit the secretion of PTH . If the profile of PTH secretion following antagonism of the CaR is rapid and transient then this should promote the formation of new bone.…”

Section: Introductionmentioning

confidence: 97%

Antagonists of the Calcium Receptor. 2. Amino Alcohol-Based Parathyroid Hormone Secretagogues

Marquis¹,

Lago²,

Callahan³

et al. 2009

J. Med. Chem.

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When administered as a single agent to rats, the previously reported calcium receptor antagonist 3 elicited a sustained elevation of plasma PTH resulting in no increase in overall bone mineral density. The lack of a bone building effect for analogue 3 was attributed to the large volume of distribution (V(dss)(rat) = 11 L/kg), producing a protracted plasma PTH profile. Incorporation of a carboxylic acid functionality into the amino alcohol template led to the identification of 12 with a lower volume of distribution (V(dss)(12) = 1.18 L/kg) and a shorter half-life. The zwitterionic nature of antagonist 12 necessitated the utility of an ester prodrug approach to increase overall permeability. Antagonist 12 elicited a rapid and transient increase in circulating levels of PTH following oral dosing of the ester prodrug 11 in the dog. The magnitude and duration of the increases in plasma levels of PTH would be expected to stimulate new bone formation.

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Design, New Synthesis, and Calcilytic Activity of Substituted 3H‐Pyrimidin‐4‐ones.

Cited by 4 publications

References 1 publication

Emerging Targets in Osteoporosis Disease Modification

Emerging Targets in Osteoporosis Disease Modification

Antagonists of the Calcium Receptor I. Amino Alcohol-Based Parathyroid Hormone Secretagogues

Antagonists of the Calcium Receptor. 2. Amino Alcohol-Based Parathyroid Hormone Secretagogues

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