17β-carboxamide steroids – in vitro prediction of human skin permeability and retention using PAMPA technique

Dobričić, Vladimir; Marković, Bojan; Nikolic, Katarina; Savić, Vladimir; Vladimirov, Sote; Čudina, Olivera

doi:10.1016/j.ejps.2013.10.017

Cited by 32 publications

(24 citation statements)

References 25 publications

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“…The first commercially available PAMPA for performing penetration studies is the skin-PAMPA, as supplied by Pion Inc. Skin-PAMPA consists of a complete test system, including UV reader, as well as required technical support and is already in use for determination of temperature and protein-binding effects, for evaluation of new compounds and for predictive approaches studying quantitative structurepermeability relationships (Akamatsu et al, 2009;Bujard et al, 2014;Dobricic et al, 2014;Markovic et al, 2012;Vizseralek et al, 2014;Vucicevic et al, 2015). In contrast, the skin-mimicking artificial membrane setup Strat-M™ (Merck Millipore, USA) is composed of multiple layers of polyether sulfone, which is compatible with Franz chamber setups.…”

Section: Synthetic Membrane Systemsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Section: Synthetic Membrane Systemsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

122

103

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“…17β‐Carboxamide steroids selected in molecular docking studies were previously synthesized using a single‐step procedure (1‐ethyl‐3‐(3‐dimethylaminopropyl)carbodiimide (EDC), 1‐hydroxybenzotriazole (HOBt), and triethylamine (TEA)) and structurally characterized . In this study, alternative two‐step synthesis of selected compounds, based on the modification of the procedure proposed by Formstecher et al , was presented.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, alternative two‐step synthesis of selected compounds, based on the modification of the procedure proposed by Formstecher et al , was presented. Reaction yields are presented in Table and compared with the yields of single‐step synthesis of these compounds .…”

Section: Resultsmentioning

confidence: 99%

“…MPEA and other compounds selected in this study (except PP) should not have significantly higher permeability through human skin than dexamethasone . Having lower EC 50 values than dexamethasone, these derivatives could be applied in much lower concentrations, which reduces the possibility of systemic side effects occurrence.…”

Section: Resultsmentioning

confidence: 99%

“…Cortienic acids, which were used for the synthesis of selected 17β‐carboxamide steroids, had been synthesized in our previous work . Methyl ester of L ‐alanine was purchased from Tokyo Chemical Industry (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Design, Synthesis, and Local Anti‐Inflammatory Activity of 17β‐Carboxamide Derivatives of Glucocorticoids

Dobričić

Marković

Milenković

et al. 2014

Archiv der Pharmazie

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Molecular docking studies were performed on 18 17β-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17β-carboxamide steroids with potentially better biological profile than dexamethasone.

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Evaluation of Biological Activity and Computer‐Aided Design of New Soft Glucocorticoids

Dobričić

Jacević

Vucicevic

et al. 2017

Archiv der Pharmazie

Self Cite

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Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity.

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17β-carboxamide steroids – in vitro prediction of human skin permeability and retention using PAMPA technique

Cited by 32 publications

References 25 publications

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Design, Synthesis, and Local Anti‐Inflammatory Activity of 17β‐Carboxamide Derivatives of Glucocorticoids

Evaluation of Biological Activity and Computer‐Aided Design of New Soft Glucocorticoids

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