Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate

  title={Soft drugs—10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: Loteprednol etabonate},
  author={Pascal Druzgala and Guenther Hochhaus and NICHOLAS S. Bodor},
  journal={The Journal of Steroid Biochemistry and Molecular Biology},
An improved synthesis of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene 17 beta-carboxylate) was achieved. The design of the new type of glucocorticoid was based on the soft drug concept. The relative binding affinities of loteprednol and its putative metabolites (PJ90 and PJ91) to rat lung type II glucocorticoid receptor were determined in a competitive binding experiment with [3H]triamicinolone acetonide. The medium contained cortienic… 
Pharmacokinetic characterization and tissue distribution of the new glucocorticoid soft drug loteprednol etabonate in rats and dogs.
Levels of intact drug and metabolites were highest in liver and kidney, whereas significantly lower levels were found in other investigated organs (lung, brain, heart).
Structural studies of loteprednol etabonate and other analogs of prednisolone using NMR techniques
The stereochemical structure of loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carboxylate, 1), a soft corticosteroid antiinflammatory drug, was proved to be analogous to prednisolone.
Budesonide and Ciclesonide: Effect of Tissue Binding on Pulmonary Receptor Binding
The PK/PD model predicted lower receptor occupancy in the lung and the systemic tissues when a drug with pronounced binding was inhaled, including des-CIC, which was predicted to be lower than BUD.
Glucocorticoid receptor binding: A biphasic dependence on molecular size as revealed by the bilinear LinBiExp model
A comprehensive quantitative analysis of relative RBA data obtained from more than a hundred active structures suggests binding is strongest for corticosteroids close to an ideal size that is large enough to provide as large nonspecific (van der Waals-type) interactions as possible, but is not too large to have difficulty fitting due to size-limitations at the binding site.
17β-carboxamide steroids--in vitro prediction of human skin permeability and retention using PAMPA technique.
Based on the 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.
Novel steroid spiro enones: condensation of prednisolone derivatives with diethyl oxalate☆
Because the corresponding acid metabolites of two representative spiro enone esters gave no activity in either the binding assay or the nitric oxide generation test, the novel steroids are probably antedrugs, and the reduced potency suggests that the rigid spiro structure is unfavorable to anti-inflammatory activities.
Soft Drugs 19. Pharmacokinetics, Metabolism and Excretion of a Novel Soft Corticosteroid, Loteprednol Etabonate, in Rats
The results indicate that LE absorbed systemically, after topical administration, can be rapidly transformed to the inactive metabolites, and eliminated from the body mainly through the bile and urine.
Pharmacokinetics and delta1-cortienic acid excretion after intravenous administration of prednisolone and loteprednol etabonate in rats.
Detailed pharmacokinetic studies in rats were performed to compare the PK of prednisolone (PRN) and loteprednol etabonate (LE) as well as their common inactive metabolite delta1-cortienic acid (delta1-CA), and to investigate the excretion of delta 1-CA after PRN and LE administration.
An HPLC method to evaluate purity of a steroidal drug, loteprednol etabonate.
A high-performance liquid chromatographic method was validated to evaluate purity of loteprednol etabonate and its four related substances, major process impurities and degradation products (PJ-90, PJ-91, LE-11-keto and LE-methyl ester) were well resolved using a phenyl-stationary phase under isocratic conditions.
Development of simultaneous quantification method of loteprednol etabonate (LE) and its acidic metabolites, and analysis of LE metabolism in rat
Loteprednol etabonate is a soft corticosteroid with two labile ester bonds at 17α- and 17β-positions that disappears upon hydrolysis of either ester bond, producing the inactive metabolite, Δ1-cortienic acid (Δ1-CA).


Correlation between chemical structure, receptor binding, and biological activity of some novel, highly active, 16 alpha, 17 alpha-acetal-substituted glucocorticoids.
The affinity for the receptor in vitro was closely correlated to the topical glucocorticoid activity in vivo for the 12 steroids compared, which supports the contention that in vitro tests for receptor affinity are useful when screening for agonists among steroids with the present type of structures.
Steroid side-chain modification and receptor affinity: binding of synthetic derivatives of corticoids to human spleen tumor and rat liver glucocorticoid receptors.
A series of side-chain modified natural and synthetic corticoids bind with similar affinities to human spleen tumor and rat liver glucocorticoid receptors, confirming the hypothesis that receptor binding involves a specific conformation of the side- chain.
Glucocorticoids and cultured human skin cells: specific intracellular binding and structure‐activity relationships
  • M. Ponec
  • Biology, Medicine
    The British journal of dermatology
  • 1982
Use of cytosol fractions of both cultured human skin fibroblasts and epidermal keratinocytes contain macromolecules that bind glucocorticoids with high affinity and the structure‐binding relationship studies revealed the relative contribution of various substituents on the steroid molecule for the binding affinity of the steroids.
Formation of covalent adducts between cortisol and 16 alpha-hydroxyestrone and protein: possible role in the pathogenesis of cortisol toxicity and systemic lupus erythematosus.
It is proposed that the formation of covalent steroid-protein adducts is a generalized phenomenon which may contribute to the pathological effects produced by elevated levels of certain endogenous steroids.
The vasoconstrictor assay for topical steroids has been modified and extended so that it may be used to screen for activity and to determine bioavailability. The precision, sensitivity and
Designing safer drugs based on the soft drug approach
In the general drug design process, one starts with a known bioactive molecule which is used as the lead compound and then undertakes structural moditiciltions either by the gmup or biotimctional
Variations in the levels of cytoplasmic glucocorticoid receptors in lungs of various species at different developmental stages.
Cytoplasmic fractions obtained from lungs of several animal species at different stages of development were examined for dexamethasone receptors and lower but significant levels of the dexamETHasone binding component were found in lungs of mature rabbits but it could not be detected in lungs in adult rats, mice, hamsters or guinea pigs.
Atrophy of the skin
  • I. Sneddon
  • Medicine
    The British journal of dermatology
  • 1976
The topical application of corticosteroids has enabled the control of so many dermatoses that one should preserve a balanced view on the occasional harmful effects which occur as a result of their abuse, but one should be especially careful in prescribing strong steroids for children and adolescents.
Chlorosulfates as Reagents in the Synthesis of Carboxylic Acid Esters Under Phase-Transfer Conditions
Abstract During a search for a satisfactory synthesis of chloromethyl esters 1 of certain β-lactam antibiotics, e.g. penicillanic acid sulfone, we discovered that chloromethyl chlorosulfate1 (4) is
Cushing's syndrome and pituitary-adrenal suppression due to clobetasol propionate.
Widespread application of clobetasol propionate resulted in suppression of the hypothalamic pituitary axis in four patients. Three patients showed Cushigoid features and developed symptoms of