New steroidal anti-inflammatory drugs

Lee, Henry J.; Heiman, Ann S.; Taraporewala, Irach B.

doi:10.1007/978-94-009-1253-3_6

Cited by 7 publications

(5 citation statements)

References 64 publications

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“…It is a modern variant of the original Fludrocortisone can be applied topically to treat inflammation directly associated with dermatoses and psoriasis [11]. However the major market for fluticasone propionate is to treat asthma as the most important member of a large class of inhaled corticosteroids.…”

Section: Fluticasone Propionatementioning

confidence: 99%

Fluorine in health care: Organofluorine containing blockbuster drugs

O’Hagan

2010

Journal of Fluorine Chemistry

761

313

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Section: Fluticasone Propionatementioning

confidence: 99%

Fluorine in health care: Organofluorine containing blockbuster drugs

O’Hagan

2010

Journal of Fluorine Chemistry

761

313

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“…Fluticasone propionate 168 can be applied to treat inflammation associated with dermatoses and psoriasis. 108 Lee and co-workers have recently employed NFSI for the fluorination pathway of betulinic acid derivative 169, 109 according to Scheme 29. Betulinic acid derivatives 169 possess potent anti HIV activity.…”

Section: B Fluorination Of Steroids 106b and Prostaglandin Derivativesmentioning

confidence: 99%

Fluorination methods in drug discovery

2016

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Fluorination reactions of medicinal and biologically-active compounds will be discussed. Late stage fluorination strategies of medicinal targets have recently attracted considerable attention on account of the influence that the fluorine atom can impart to targets of medicinal importance, such as a modulation of lipophilicity, electronegativity, basicity and bioavailability, this latter as a consequence of membrane permeability. Therefore, the recourse to late-stage fluorine substitution on compounds with already known and relevant biological activity can provide the pharmaceutical industry with new leads with improved medicinal properties. The fluorination strategies will take into account different fluorinating reagents, nucleophilic, electrophilic and of radical nature. Diverse families of organic compounds such as (hetero)aromatic rings, and aliphatic substrates (sp 3 , sp 2 , and sp carbon atoms) will be studied in late-stage fluorination reaction strategies. The omniphobicity/lipophilicity and electrostatic interactions can be considered among the most prominent effects. Thus, introducing fluorine into an organic compound can significantly alter its biological properties.One other subtle but important effect of introducing fluorine into the backbone of a medicinal target is the inflection of acidity and basicity of the parent compound 4 , which can change, inter alia, the binding affinity, and bioavailability. Highly basic groups can have a detrimental effect on the bioavailability of a drug. Thus introducing a fluorine atom next to a basic group can reduce its basicity, enhancing its membrane permeability, and increasing bioavailability. Although the replacement of hydrogen for fluorine does not have a profound steric influence, electrostatic interactions with other groups can change conformations significantly. The replacement of hydrogen for fluorine on aromatic rings is a well-known strategy to decelerate oxidative metabolic processes by Cytochrome P450 monooxygenases. In this respect, the electron-withdrawing properties of fluorine on aromatic rings, which can slow down hydrolytic metabolism, alter reaction rates and stability of intermediates. Fluorine substitution on aromatic rings is also known to increase binding affinity, as a result of enhancing electrostatic interactions.However, it is difficult to predict the influence of fluorine substitution on the overall profile in a given situation.As numerous reports attest 1 , the number of marketed drugs that contain a fluorine atom has increased rapidly. As of 2009, the FDA-had approved >140 fluorine-containing drugs. This review article is intended to present new synthetic methodologies 9 for accomplishing fluorination reactions on molecules (drugs/prodrugs) with pharmacological activity. It is not our aim (Figure 3). would be beneficial to the syntheses. 3a.-Conversion of C Ar -H into C Ar -F BondsXu and co-workers 38 have developed an ortho C-H bond fluorination of 2-phenoxyl pyridine derivatives through a palladium-catalyzed reaction v...

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“…In an effort to circumvent the adverse clinical systemic effects, new steroidal antiinflammatory antedrugs that act locally at the site of application but are easily transformed into inactive metabolites upon entry into the systemic circulation are being synthesized and tested. [1][2][3][4][5][6][7] Our most recent efforts toward acheiving this goal include the synthesis of ll/3,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)isoxazolino [16,17-d]pregna-l,4-diene (2a) and 9-fluoro-ll/3,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)isoxazolino[l6,17-<¿]prednisolone (2b), respectively. Treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Although topical application of steroids reduces adverse systemic effects, long-term usage or application of large doses result in toxic systemic side effects. 3 Much effort has been devoted to structural modification of cortisol with hopes of increasing its potency as well as minimizing the well-documented adverse effects of glucocorticoids. The prototypic steroidal antedrugs, ester derivatives of steroid-21-oic acids, prepared by modifying the 17/3-ketol side chain of prednisolone have been shown to retain the significant local antiinflammatory activity seen following application of the parent compound but are devoid of prednisolone-like adverse systemic effects.8-10 The antedrug concept has been further applied by incorporating a metabolically labile group such as a carboxy ester or carboxamide at strategic positions on the steroid nucleus.…”

Section: Introductionmentioning

confidence: 99%

“…(t, 3, J = 7.0, 3'-C02CH2Cff3), 1.07 (s,3, I9-CH3); IR (cm'1) 1775, 1665, 1625; MS ( + H)+ 518.2. 20-Acetoxy-9-fluoro-lljS-hydroxy-3,20-dioxo-3'-(ethoxy-carbonyI)isoxazolino[16,17-d]pregna-l,4-diene (3b) was prepared from compound 2b in a manner similar to the preparation of compound 3a: mp 228-230 °C; NMR (CDCls) 7.14 (d, 1, J = 10.3, 1-Cff), 6.33 (dd, 1, J = 10.3, 2.2, 2-Cff),6.11 (br s, 1, 4-Gif),5.05 (d, 1, J = 17.6, one of 21-Cff2), 4.72 (d, 1, J = 17.6, one of 21-Cff2), 4.43 (br d, 1, J = 8.6, 11-Cff), 4.33 (q, 2, J = 7.0, 3'-C02Cff2CH3), 4.18 (br d, 1, J = 8.1, 16-Cff), 2.20 (s, 3, 21-OCOCff3), 1.56 (s, 3, 18-Cff3),1.36 (t, 3, J = 7.0,3'-C02CH2Cff3), 1.10 (s, 3,19-CH3); IR (cm"1) 1775, 1665, 1625; MS ( + H)+ 518.2.…”

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confidence: 99%

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New Steroidal Antiinflammatory Antedrugs: Steroidal [16.alpha.,17.alpha.-d]-3'-Carbethoxyisoxazolines

Kwon¹,

Heiman²,

Oriaku³

et al. 1995

J. Med. Chem.

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Novel steroidal antiinflammatory antedrugs, 11 beta,20-dihydroxy-3,20-dioxo-3'-(ethoxycarbonyl)-isoxazolino[16,17 - d]pregna-1,4-diene (2a) and 9-fluoro-11 beta,20-dihydroxy-3,20-dioxo-3'-ethoxy- carbonylisoxazolino[16,17-d]pregna-1,4-diene (2b) were prepared in 97% yield via 1,3-dipolar cycloaddition of carbethoxyformonitrile (CEFNO) to 11 beta,21-dihydroxy-3,20-dioxopregna-1,4,-16-triene (1a) and 11 beta,21-dihydroxy-3,20-dioxo-9-fluoropregna-1,4,16-triene (1b), respectively, which were prepared via five steps from prednisolone and 9-fluoroprednisolone, respectively. The treatment of steroids 2a and 2b with acetic anhydride in pyridine led to the corresponding 21-acetates 3a and 3b, respectively, in 95% yield. Dose-response profiles of the croton oil-induced ear edema bioassay in rats were used to calculate the following ID50 values (nmol/ear resulting in a 50% reduction of edema): prednisolone (P), 540 nmol; 2b, 135 nmol; and 3b, 101 nmol. Inhibition of edema did not exceed 50% following application of either 2a or 3a. Relative potency calculations indicated that 2b was 4-fold and 3b 5.3-fold more potent than the parent compound P when applied topically. No significant adverse systemic effects were seen following treatments with 3b. These results suggest that C-9-fluorination, side-chain hydroxy group esterification, and [16 alpha,17 alpha-d]-3'-carbethoxyisoxazoline additions to the conventional steroid P improve topical antiinflammatory activity without concomitant increases in adverse systemic activity.

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New steroidal anti-inflammatory drugs

Cited by 7 publications

References 64 publications

Fluorine in health care: Organofluorine containing blockbuster drugs

Fluorine in health care: Organofluorine containing blockbuster drugs

Fluorination methods in drug discovery

New Steroidal Antiinflammatory Antedrugs: Steroidal [16.alpha.,17.alpha.-d]-3'-Carbethoxyisoxazolines

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