Theoretical study of the deposition and adsorption of bisphosphonates on the 001 hydroxyapatite surface: Implications in the pathological crystallization inhibition and the bone antiresorptive action

C., David J. Fernández; Ortega‐Castro, Joaquín; Frau, Juan

doi:10.1016/j.apsusc.2016.09.029

Cited by 8 publications

(12 citation statements)

References 88 publications

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“…IP6 (the active component of SNF472) has been shown to prevent vascular calcification in a variety of animal models . This molecule has a high affinity for solid calcium salts, and rapidly binds to the surface of a forming nucleus or on the faces of a growing crystal . It acts as an inhibitor of crystallization at sub‐stoichiometric levels, since it specifically binds to the growth sites to block the calcification process and does not require binding to the entire crystal surface.…”

Section: Discussionmentioning

confidence: 99%

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Perelló

Joubert

Ferrer

et al. 2018

Brit J Clinical Pharma

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Aims SNF472 is a calcification inhibitor being developed for the treatment of cardiovascular calcification in haemodialysis (HD) and in calciphylaxis patients. This study investigated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) SNF472 in healthy volunteers (HV) and HD patients. Methods This is a first‐time‐in‐human, double‐blind, randomized, placebo‐controlled Phase I study to assess the safety, tolerability and PK of SNF472 after ascending single IV doses in HV and a single IV dose in HD patients. A pharmacodynamic analysis was performed to assess the capability of IV SNF472 to inhibit hydroxyapatite formation. Results Twenty HV and eight HD patients were enrolled. The starting dose in HV was 0.5 mg kg–1 and the dose ascended to 12.5 mg kg–1. The dose selected for HD patients was 9 mg kg–1. Safety analyses support the safety and tolerability of IV SNF472 in HD patients and HV. Most treatment‐emergent adverse events were mild in intensity. No clinically significant effects were observed on vital signs or laboratory tests. PK results were similar in HD patients and HV and indicate a lack of significant dialysability. Pharmacodynamic analyses demonstrated that SNF472 administration reduced hydroxyapatite crystallization potential in HD patients who received IV SNF472 9 mg kg–1 by 80.0 ± 2.4% (mean ± standard error of the mean, 95% CI, 75.3–84.8) compared to placebo (8.7 ± 21.0%, P < 0.001, 95% CI, –32.4 to 49.7). Conclusion The results from this study showed acceptable safety and tolerability, and lack of significant dialysability of IV SNF472. It is a potential novel treatment for cardiovascular calcification in end‐stage renal disease and calciphylaxis warranting further human studies.

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Section: Discussionmentioning

confidence: 99%

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Perelló

Joubert

Ferrer

et al. 2018

Brit J Clinical Pharma

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“…[20] Alendronate passes through one protonation and two deprotonations. [20,22] On the other hand, risedronate undergoes two or three deprotonations. [23] Information regarding theoretical modeling in vacuum and water for neutral bisphosphonates is available in the supplementary material.…”

Section: Theoretical Modelingmentioning

confidence: 99%

“…Such results are consistent with previous experimental published data, this suggests that the chemical characteristic of the nitrogen-containing bisphosphonates (N-BPs) is responsible for its biological effect and binding with hydroxyapatite surfaces. [2,14,20,21]…”

Section: Theoretical Modelingmentioning

confidence: 99%

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Bisphosphonates on Smooth TiO₂: Modeling and Characterization

et al. 2022

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This paper presents insights into surfaces properties of sputter‐deposited titania modified with bisphosphonates, including zeta potential measurements in a pH range. Functionalization was investigated through simulation and experimental approaches to model the adsorbate and evaluate structure‐response relationships. Molecules of etidronic, alendronic, and risedronic acids were investigated through density functional theory. The molecules vary their reactivity through similar structures considering different scenarios. X‐ray photoelectron spectroscopy of titania/BP systems demonstrated that functionalization occurs in a short time and resulted in a predominantly “side‐on” adsorbate configuration after two hours of immersion. Zeta potential showed the predominancy of negative charges deprotonated free phosphonates. Water contact angle demonstrated that titania surfaces are hydrophilic after overnight functionalization. Atomic force measurements of bisphosphonates layers suggested that the molecular anions follow the surface topography, unchanging the surface roughness.

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“…Therefore, many scientists are engaged to find out the liaison between the structure and the inhibition activities of phosphonate inhibitors [13][14][15][16]. The most successful method for constructing this liaison is Quantitative Structure Activity Relationship (QSAR) method, which is used to predict the drug activities and information for designing new potential drugs [17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

QSAR Models for Nitrogen Containing Monophosphonate and Bisphosphonate Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors Based on Monte Carlo Method

Kumar

Sindhu³

et al. 2018

Drug Res (Stuttg)

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Human farnesyl pyrophosphate synthase (hFPPS) is a well-settled therapeutic target and it is an enzyme of the mevalonate pathway which catalyzes the biosynthesis of the C-15 isoprenoid farnesyl pyrophosphate. QSAR studies by using Monte Carlo method for human farnesyl pyrophosphate synthase inhibitors has been carried out using balance of correlation technique with Index of ideality correlation. For construction of QSAR models, six random splits were prepared from the data of 73 phosphonates and hybrid optimal descriptors procured from graph (HFG) and SMILES based notations were employed. The developed QSAR models have robustness, good fitting ability, generalizability and internal predictive ability. The external predictive ability has been certified by testing various precedents. The values of R, IIC, Q and ∆R for the best model are 0.9304, 0.9614, 0.9061 and 0.0861 respectively. The developed QSAR models met with the specified standards given in OECD guideline and applicability domain. The structural feature promoters for the end point increase and promoters for end point decrease have been extracted. The predicted pIC for the new proposed compounds have also been reported.

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Theoretical study of the deposition and adsorption of bisphosphonates on the 001 hydroxyapatite surface: Implications in the pathological crystallization inhibition and the bone antiresorptive action

Cited by 8 publications

References 88 publications

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Bisphosphonates on Smooth TiO₂: Modeling and Characterization

QSAR Models for Nitrogen Containing Monophosphonate and Bisphosphonate Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors Based on Monte Carlo Method

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Theoretical study of the deposition and adsorption of bisphosphonates on the 001 hydroxyapatite surface: Implications in the pathological crystallization inhibition and the bone antiresorptive action

Cited by 8 publications

References 88 publications

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

First‐time‐in‐human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification

Bisphosphonates on Smooth TiO2: Modeling and Characterization

QSAR Models for Nitrogen Containing Monophosphonate and Bisphosphonate Derivatives as Human Farnesyl Pyrophosphate Synthase Inhibitors Based on Monte Carlo Method

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Bisphosphonates on Smooth TiO₂: Modeling and Characterization