17β-carboxamide steroids--in vitro prediction of human skin permeability and retention using PAMPA technique.
In this paper, twenty-two 17β-carboxamide steroids were synthesized from five corticosteroids (hydrocortisone, prednisolone, methylprednisolone, dexamethasone and betamethasone) in two steps. The first step was periodic acid oxydation of these corticosteroids to corresponding cortienic acids and the second step was amidation of thus obtained cortienic acids with esterified l-amino acids. These compounds are potential soft corticosteroids with local anti-inflammatory activity in the skin. Parallel artificial membrane permeability assay (PAMPA) was applied in order to predict permeability and retention of these compounds in human skin. Comparison of permeability and retention parameters between 17β-carboxamide steroids and corresponding corticosteroids was performed. Compounds with significantly higher retention were identified and the derivative that does not have significantly higher permeability was underlined. Molecular structures of all compounds were optimized by use of Gaussian semiempirical/PM3 method. Geometrical, thermodynamic, physicochemical and electronical molecular parameters of the optimized structures were calculated and quantitative structure-property relationship (QSPR) analysis was performed in order to explain permeability and retention of these compounds. ANN-, PLS- and MLR-QSPR models were created. Quality of these models was evaluated by commonly used statistical parameters and the most reliable models were selected. Analyzing descriptors in the selected models, main molecular properties that influence permeability and retention in the PAMPA artificial membrane were identified. Based on these data, further structural modifications could be applied in order to increase retention without significant increase of permeability, which can positively affect potential local anti-inflammatory activity of these compounds. Selected QSPR models could be used as in silico tool for predicting human skin permeability and retention of novel 17β-carboxamide steroids without performing PAMPA experiments.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia. Electronic address: vladimir@pharmacy.bg.ac.rs.
Vladimir
V
Dobričić
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Bojan
B
Marković
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Katarina
K
Nikolic
Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Vladimir
V
Savić
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Sote
S
Vladimirov
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
Olivera
O
Čudina
D000305:Adrenal Cortex Hormones / Q000737:chemistry / Q000378:metabolism*; D000577:Amides / Q000737:chemistry / Q000378:metabolism*; D000734:Androstenediols / Q000737:chemistry; D006801:Humans; D008567:Membranes, Artificial; D010539:Permeability; D021281:Quantitative Structure-Activity Relationship; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption
D000305:Adrenal Cortex Hormones; D000577:Amides; D000734:Androstenediols; D008567:Membranes, Artificial; C026548:cortienic acid
Human skin permeability and retention; PAMPA; Quantitative structure–property relationship; Soft corticosteroids