Anti‐Inflammatory Steroids

Avery, Mitchell A.; Woolfrey, John

doi:10.1002/0471266949.bmc056

Cited by 14 publications

(12 citation statements)

References 276 publications

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“…The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators. drug design ͉ AlleGrow ͉ glucocorticoid modulation ͉ intranasal glucocorticoid S ince the discovery of the remarkable anti-inflammatory properties of the natural glucocorticoid cortisol 1 in the 1940s (1) this steroidal template has been the subject of extensive optimization to deliver compounds with enhanced potency, selectivity, and pharmacokinetic properties (Scheme 1) (2). The most recent derivative to emerge from this effort is fluticasone furoate 2, which as Veramyst/Avamys offers highly effective once-daily treatment for both nasal and ocular symptoms of seasonal and perennial allergic rhinitis (3,4).…”

mentioning

confidence: 99%

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Biggadike

Bledsoe²,

Coe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Crystallography and computer modeling have been used to exploit a previously unexplored channel in the glucocorticoid receptor (GR). Highly potent, nonsteroidal indazole amides showing excellent complementarity to the channel were designed with the assistance of the computational technique AlleGrow. The accuracy of the design process was demonstrated through crystallographic structural determination of the GR ligand-binding domain-agonist complex of the D-prolinamide derivative 11. The utility of the channel was further exemplified through the design of a potent phenylindazole in which structural motifs, seen to interact with the traditional GR ligand pocket, were abandoned and replaced by interactions within the new channel. Occupation of the channel was confirmed with a second GR crystal structure of this truncated D-alaninamide derivative 13. Compound 11 displays properties compatible with development as an intranasal solution formulation, whereas oral bioavailability has been demonstrated with a related truncated exemplar 14. Data with the pyrrolidinone amide 12 demonstrate the potential for further elaboration within the ''meta'' channel to deliver compounds with selectivity for the desired transrepressive activity of glucocorticoids. The discovery of these interactions with this important receptor offers significant opportunities for the design of novel GR modulators. drug design ͉ AlleGrow ͉ glucocorticoid modulation ͉ intranasal glucocorticoid

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mentioning

confidence: 99%

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Biggadike

Bledsoe²,

Coe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Corticosteroids exert profound biologic effects in almost every organ; hence, they are one of the most widely used drug classes in a bewildering range of clinical diseases-mainly for their anti-inflammatory and immunosuppressive effects [149,150]. Unfortunately, systemic side effects, which typically include myopathy, osteoporosis, hypertension, insulin resistance, weight gain, fat redistribution, increased IOP, growth inhibition, and others in a dose-dependent manner [151][152][153][154][155][156], seriously limit their application.…”

Section: Softmentioning

confidence: 99%

“…In this series, hydrolysis of a phosphate ester and not that of a carboxylic ester was expected to provide metabolic inactivation. The P-OEt ester bond of the ethyl ester turned out to be stable in human plasma, but di-and trifluoroethyl esters (149b, 149c) hydrolyzed rapidly (t 1/2 of 10 and <1 min, respectively) and resulted in inactive metabolites (151, 152) via a spontaneously decomposing phosphonic acid intermediate (150). It seems that presence of an electron-withdrawing substituent that can cause an increase in the positive charge on the P atom is needed to facilitate enzymatic hydrolysis of these compounds.…”

Section: Soft Matrix Metalloproteinase (Mmp)mentioning

confidence: 99%

Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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Retrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.

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“…They are currently the drugs of choice for the treatment of several diseases, despite their adverse side effects (Avery, Woolfrey, 1997).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of HPLC method for analysis of dexamethasone acetate in microemulsions

Urban

Mainardes

Gremião

2009

Braz. J. Pharm. Sci.

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A simple, rapid, accurate and sensitive method was developed for quantitative analysis of dexamethasone acetate in microemulsions using high performance liquid chromatography (HPLC) with UV detection. The chromatography parameters were stainless steel Lichrospher 100 RP-18 column (250 mm x 4 mm i.d., 5 µm particle size), at 30 ± 2 ºC. The isocratic mobile phase was methanol:water (65:35; v/v) at a flow rate of at 1.0 mL.min -1. The determinations were performed using UV-Vis detector set at 239 nm. Samples were prepared with methanol and the volume injected was 20 µL. The analytical curve was linear (r 2 0.9995) over a wide concentration range (2.0-30.0 µg.mL -1 ). The presence of components of the microemulsion did not interfere in the results of the analysis. The method showed adequate precision, with a relative standard deviation (RSD) smaller than 3%. The accuracy was analyzed by adding a standard drug and good recovery values were obtained for all drug concentrations used. The HPLC method developed in this study showed specificity and selectivity with linearity in the working range and good precision and accuracy, making it very suitable for quantification of dexamethasone in microemulsions. The analytical procedure is reliable and offers advantages in terms of speed and low cost of reagents. Um método simples, rápido, preciso e sensível foi desenvolvido para a análise quantitativa de acetato de dexametasona em microemulsões usando cromatografia líquida de alta eficiência (CLAE). Os parâmetros cromatográficos foram: coluna cromatográfica Lichrospher 100 RP-18, (250 mm x 4 mm i.d., 5 µm partícula tamanho), com temperatura de coluna de 30 ± 2 ºC. A fase móvel foi composta de metanol: água (65:35; v/v) com fluxo isocrático de 1 mL.min -1 e volume de injeção de 20 µL. As determinações foram realizadas utilizando detector UV-Vis no comprimento de onda de 239 nm. A curva analítica mostrou-se linear (r 2 0,999) em uma ampla faixa de concentração (2,0-30,0 µg.mL -1 ). A presença de componentes da microemulsão não interferiu nos resultados da análise. O método mostrou precisão adequada, com desvio padrão relativo menor que 3%. A exatidão foi analisada pela adição de padrões do fármaco e valores de recuperação dentro dos limites recomendáveis foram obtidos para todas as concentrações estudadas. O método por CLAE mostrou especificidade e seletividade com linearidade dentro da faixa de concentração utilizada e precisão e exatidão que tornam o método adequado para a análise de dexametasona em microemulsões. O procedimento analítico é fidedigno e oferece vantagens em termos de velocidade e custo de reativos. Unitermos: Acetato de dexametasona/determinação. Microemulsões/análise quantitativa. Cromatografia líquida de alta eficiência/análise quantitativa. Método de análise/validação.

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Anti‐Inflammatory Steroids

Cited by 14 publications

References 276 publications

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor

Retrometabolism‐Based Drug Design and Targeting

Development and validation of HPLC method for analysis of dexamethasone acetate in microemulsions

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