Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis

Arns, Steve; Gibe, Romelo; Moreau, Anne; Morshed, M. Monzur; Young, Robert N.

doi:10.1016/j.bmc.2012.01.024

Cited by 42 publications

(66 citation statements)

References 17 publications

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“…With gradual cleavage by local hydrolytic enzymes, the amount of freed EP4a varies with time after administration of the conjugate. As demonstrated by Arns et al 221 ( Figure 1-20), approximately 6% of the initial dose binds to bone, which then undergoes rapid cleavage for release of EP4a. Approximately 66% of the bone--bound conjugate is cleaved within the first week after administration.…”

Section: Dosing Regimementioning

confidence: 87%

“…Arns et al 221 conducted several experiments to determine the conjugate's metabolic characteristics. First, they incubated the conjugate in fresh rat plasma at 37°C to assess total hydrolysis, and showed that there was a 6.2% hydrolysis of the conjugate after 24 hours.…”

Section: In Vivo Uptake and Releasementioning

confidence: 99%

“…Moreover, the liberated EP4a can promote bone formation while ALN remains bound to bone to inhibit resorption, enabling the drug to have dual--acting effects. A previous study had established the metabolic stability of ALN--LK--EP4a as well as the gradual release of EP4a from the bone--bound conjugate in vivo 221 , setting the stage for the current work to investigate its in vivo efficacy. In order to examine the in vivo therapeutic effects of the new drug in treating postmenopausal osteoporosis, an animal model of the disease is required.…”

Section: Review Of Study Objectivesmentioning

confidence: 99%

“…The binding of ALN to bone mineral is known to be robust 58 , and deposits the absorbed portion of the inactive conjugate on bone surfaces following administration. In addition, the cleavage of EP4a via enzymatic action in vivo has been shown to occur gradually over 2 weeks with a 5--day half--life 221 , which releases small quantities of EP4a at a time. Given these conditions, the local release of EP4a in bone sites thus more closely resembles continuous administration rather than the intermittent dosing applied during the study.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Blue line denotes surface--bound conjugate, while red line denotes EP4a release during first week after administration. Quantities are determined using the radio--labeling results of study by Arns et al 221 , and the amount of bone--bound conjugate is calculated by taking 6% of each administered dose for CL and CH. The amount of EP4a release is determined by the taking the percentage reduction of bone--bound conjugate after 1 week, which is 4% of initial dose based on results by Arns et al Calculations also assume that half of the remaining uncleaved conjugate after 1 week becomes embedded into bone, while the other half is added to the bone--bound conjugate from the next treatment dose.…”

Section: Dosing Regimementioning

confidence: 99%

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Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Liu¹,

Young²,

Grynpas³

2013

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Postmenopausal osteoporosis is a disease characterized by bone loss and increased risk of fracture, and represents a significant burden on the Canadian health care system. Current treatments lack the ability to simultaneously address the therapeutic needs for promoting bone formation and inhibiting resorption. Our approach employs a novel conjugate drug in which an anabolic agent (EP4 receptor agonist) is reversibly joined with an anti--resorptive agent (alendronate) through a linker. This allows the bone--targeting ability of alendronate to deliver the EP4 agonist to bone sites, thereby mitigating the side effects associated with systemic administration of the EP4 agonist. This study investigated the in vivo efficacy of this drug in a curative experiment to treat postmenopausal osteoporosis using an ovariectomized rat model. Results showed that conjugate treatment dose--dependently stimulated bone formation and restored ovariectomy--induced bone loss, and conjugation between alendronate and the EP4 agonist was crucial to the drug's anabolic effect.iii

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Section: Dosing Regimementioning

confidence: 87%

Section: In Vivo Uptake and Releasementioning

confidence: 99%

Section: Review Of Study Objectivesmentioning

confidence: 99%

Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Dosing Regimementioning

confidence: 99%

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Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Liu¹,

Young²,

Grynpas³

2013

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Bisphosphonate‐Functionalized Imaging Agents, Anti‐Tumor Agents and Nanocarriers for Treatment of Bone Cancer

Nadar

Margiotta

Iafisco

et al. 2017

Adv Healthcare Materials

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Bone metastases result from the invasion of primary tumors to bone. Current treatment modalities include local treatments such as surgery and radiotherapy, while systemic treatments include chemotherapy and (palliative) treatment of skeletal metastases. Nevertheless, once bone metastases have been established they remain incurable leading to morbidity and mortality. Bisphosphonates are a well-established class of drugs, which are increasingly applied in the treatment of bone cancers owing to their effective inhibition of tumor cells and suppression of bone metastases. The increased understanding of the mechanism of action of bisphosphonates on bone and tumor cells has prompted the development of novel bisphosphonate-functionalized imaging and therapeutic agents. This review provides an update on the preclinical efficacy of bisphosphonate-functionalized fluorophore, anti-tumor agents and nanocarriers for the treatment of bone metastases. After an overview of the general characteristics of bisphosphonates and their mechanisms of action, an outline is provided on the various conjugation strategies that have become available to functionalize imaging agents, anti-tumor agents and nanocarriers with bisphosphonates. Finally, the efficacy of these bisphosphonate-modified agents and carriers in preclinical studies is evaluated by reviewing their potential to target tumors and inhibit tumor growth in clinically relevant animal models for the treatment of bone cancer.

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One‐Pot Synthesis of Fluorovinyl Acetates and β,β‐Difluoro Carboxylates from a Hypervalent Iodine and Hydrogen Fluoride‐Based Fluorination Reagent

Zhang

2016

Adv Synth Catal

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A new strategy for the synthesis of fluorovinyl acetates and β,β‐difluoro carboxylates using a hypervalent iodine and hydrogen fluoride‐based fluorination reagent is established through a silver‐catalyzed one‐pot reaction involving formation of carbon‐oxygen and carbon‐nitrogen bonds. The generated fluoroalkenes substituted with the carbon‐oxygen and carbon‐nitrogen bond on the β‐position have the potential to be transformed into various products which would be difficult to obtain via direct fluorination.magnified image

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Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis

Cited by 42 publications

References 17 publications

Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Effects of a new conjugate drug in a rat model of postmenopausal osteoporosis

Bisphosphonate‐Functionalized Imaging Agents, Anti‐Tumor Agents and Nanocarriers for Treatment of Bone Cancer

One‐Pot Synthesis of Fluorovinyl Acetates and β,β‐Difluoro Carboxylates from a Hypervalent Iodine and Hydrogen Fluoride‐Based Fluorination Reagent

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