An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation

Kumar, Sanjay; Matheny, Christopher; Hoffman, Sandra J.; Marquis, Robert W.; Schultz, Maggie; Liang, Xiaoguang; Vasko, J.; Stroup, George B.; Vaden, Vernal R.; Haley, Hyking; Fox, John; DelMar, Eric G.; Nemeth, Edward F.; Lago, Amparo M.; Callahan, James F.; Bhatnagar, Pradip K.; Huffman, William F.; Gowen, Maxine; Yi, Bingming; Danoff, Theodore M.; Fitzpatrick, Lorraine A.

doi:10.1016/j.bone.2009.09.028

Cited by 73 publications

(65 citation statements)

References 28 publications

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“…With the very closely related drug/ prodrug pair X in Table 13 (SB-423562 and its orally bioavailable precursor SB-423557), Kumar et al (2010) have then also found a transient increase in circulating PTH levels in several species, including humans. In an ovariectomized rat model of bone loss, daily oral administration of the prodrug SB-423557 then indeed increased bone formation and bone strength (Kumar et al, 2010). Long-term administration of the drug did not increase parathyroid cell proliferation, a theoretically possible side effect of calcilytic drugs.…”

Section: In Vivo Effects Of Allosteric Calcium Sensing Receptor Momentioning

confidence: 99%

“…An improved bioavailability was obtained with the corresponding ester prodrug (IX, r ϭ ethyl), which elicited a rapid and transient increase in PTH levels after oral administration in the dog (Marquis et al, 2009b). With the very closely related drug/ prodrug pair X in Table 13 (SB-423562 and its orally bioavailable precursor SB-423557), Kumar et al (2010) have then also found a transient increase in circulating PTH levels in several species, including humans. In an ovariectomized rat model of bone loss, daily oral administration of the prodrug SB-423557 then indeed increased bone formation and bone strength (Kumar et al, 2010).…”

Section: In Vivo Effects Of Allosteric Calcium Sensing Receptor Momentioning

confidence: 99%

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Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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Section: In Vivo Effects Of Allosteric Calcium Sensing Receptor Momentioning

confidence: 99%

Section: In Vivo Effects Of Allosteric Calcium Sensing Receptor Momentioning

confidence: 99%

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

2011

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“…In aged OVX rats with established osteopenia, a calcilytic molecule was shown to increase PTH secretion and bone mass in the presence of an antiresorptive agent (25). Recently, an orally active CaSR antagonist was shown to increase bone formation and bone strength in OVX rats (26). Thus, calcilytic molecules may prove to be useful in promoting bone formation in osteopenic disorders.…”

Section: Present Anabolic Therapiesmentioning

confidence: 99%

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

Marie¹,

Kassem²

2011

European Journal of Endocrinology

191

143

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Objective: Age-related bone loss is associated with significant changes in bone remodeling characterized by decreased trabecular and periosteal bone formation relative to bone resorption, resulting in bone fragility and increased risk of fractures. Prevention or reversal of age-related decrease in bone mass and increase in bone fragility has been based on inhibition of bone resorption using anticatabolic drugs. The current challenge is to promote osteoblastogenesis and bone formation to prevent age-related bone deterioration. Methods: A limited number of approved therapeutic molecules are available to activate bone formation. Therefore, there is a need for anabolic drugs that promote bone matrix apposition at the endosteal, endocortical, and periosteal envelopes by increasing the number of osteoblast precursor cells and/or the function of mature osteoblasts. In this study, we review current therapeutics promoting bone formation and anabolic molecules targeting signaling pathways involved in osteoblastogenesis, based on selected full-text articles searched on Medline search from 1990 to 2010. Results and discussion: We present current therapeutic approaches focused on intermittent parathyroid hormone and Wnt signaling agonists/antagonists. We also discuss novel approaches for prevention and treatment of defective bone formation and bone loss associated with aging and osteoporosis. These strategies targeting osteoblastic cell functions may prove to be useful in promoting bone formation and improving bone strength in the aging population.

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“…Such negative allosteric compounds are being studied for their potential use as anabolic agents in the treatment of osteoporosis [132]. Recently, it was shown in an ovariectomized rat model of bone loss that daily oral administration of the calcilytic prodrug SB-423557 increased bone formation and bone strength without affecting parathyroid cell proliferation [133]. Moreover, in aged female rats, the ATF936 calcilytic drug induced increased bone formation and, in healthy humans, a single dose triggered peak PTH levels and was well-tolerated [134].…”

Section: Negative Allosteric Modulatorsmentioning

confidence: 99%

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

Diez-Fraile

Lammens²,

Benoit³

et al. 2012

CMM

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Abstract:The calcium-sensing receptor (CaSR) belongs to the evolutionarily conserved family of plasma membrane G protein-coupled receptors (GPCRs). Early studies identified an essential role for the CaSR in systemic calcium homeostasis through its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that influence parathyroid hormone secretion. However, the presence of CaSR protein in tissues is not directly involved in regulating mineral ion homeostasis points to a role for the CaSR in other cellular functions including the control of cellular proliferation, differentiation and apoptosis. This position at the crossroads of cellular fate designates the CaSR as an interesting study subject is likely to be involved in a variety of previously unconsidered human pathologies, including cancer, atherosclerosis and Alzheimer's disease. Here, we will review the recent discoveries regarding the relevance of CaSR signaling in development and disease. Furthermore, we will discuss the rational for developing and using CaSR-based therapeutics.

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An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation

Cited by 73 publications

References 28 publications

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

Osteoblasts in osteoporosis: past, emerging, and future anabolic targets

The Calcium-Sensing Receptor as a Regulator of Cellular Fate in Normal and Pathological Conditions

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