Development of fluticasone propionate and comparison with other inhaled corticosteroids

doi:10.1016/S0091-6749(98)70155-1

Journal of Allergy and Clinical Immunology

Volume 101, Issue 4, Supplement, April 1998, Pages S434-S439

https://doi.org/10.1016/S0091-6749(98)70155-1 Get rights and content

Abstract

Fluticasone propionate (FP) is a trifluorinated glucocorticoid based on the androstane nucleus. It was selected for development from structure-activity relationships (topical anti-inflammatory, cutaneous vasoconstriction, and hypothalamic-pituitary-adrenal axis suppression) of a series of 17β-carbothioates. FP is 3-, 300-, and 1000-fold more lipophilic than beclomethasone dipropionate, budesonide, and triamcinolone acetonide, respectively. FP has an absolute affinity (K_D) for the glucocorticoid receptor of 0.5 nmol/L and a relative receptor affinity 1.5-fold higher than beclomethasone-17- monopropionate (17-BMP) and mometasone furoate, 3-fold higher than budesonide, and 20-fold higher than flunisolide and triamcinolone acetonide. The rate of association of FP with the receptor is faster and the rate of dissociation slower than other corticosteroids. The resulting half-life of the FP active steroid-receptor complex is >10 hours, compared with approximately 5, 7.5, and 4 hours for budesonide, 17-BMP, and triamcinolone acetonide, respectively. FP has high selectivity for the glucocorticoid receptor, with little or no activity at other steroid receptors. FP is more potent than beclomethasone dipropionate, budesonide, triamcinolone acetonide, and mometasone furoate in inhibiting human T-cell migration and proliferation, inhibiting CD4+ T-cell cytokine and basophil histamine release, attenuating adhesion molecule expression, stimulating inflammatory cell apoptosis, and inducing cellular antiprotease release. In asthma patients, FP decreases the number of CD3+, CD4+, CD8+, and CD25+ T cells, mast cells, and eosinophils in bronchial biopsies, in addition to suppressing CD1a-dendritic and IgE+ cells and HLA-DR. FP, therefore, has a good pharmacologic profile for a topical steroid with increased intrinsic glucocorticoid potency and potent anti-inflammatory activity. (J Allergy Clin Immunol 1998;101:S434-9.)

Section snippets

Development of fluticasone propionate

The development of fluticasone propionate was an attempt to produce a potent corticosteroid that exhibited improved airway selectivity (Table I) compared with earlier compounds.

. Criteria for improved airway selectivity of corticosteroids

Pharmacodynamics

• High glucocorticoid receptor affinity

• Optimal glucocorticoid receptor kinetics

• High intrinsic steroid potency/high topical anti-inflammatory activity

• High glucocorticoid receptor specificity

Pharmacokinetics

• Low oral bioavailability

•

Receptor Pharmacology

FP has a high affinity for the human lung GR (0.5 nmol/L),¹⁴ which is 1.5-fold higher than 17-BMP and mometasone furoate, 3-fold higher than budesonide, and 10-fold higher than triamcinolone acetonide and flunisolide (Table III). Unlike budesonide, which is a racemic mixture of 22R and 22S enantiomers, FP does not have a chiral center and therefore the measured affinity represents the affinity of the molecule and not the contribution of the individual enantiomers. In contrast to 17-BMP, the

Anti-inflammatory activity

The steroid receptor profile of FP imparts a high topical anti-inflammatory activity. The active FP-GR complex binds to the GRE on target genes (EC₅₀ = 3 nmol/L) or interacts directly with activating protein-1 and/or nuclear factor-kB transcription factors (EC₅₀ range 0.01 to 0.1 nmol/L) at significantly lower concentrations than either dexamethasone or budesonide.¹⁶ This has a good correlation with the respective potency of FP in inhibiting GRE-dependent cytokine (IL-6, IL-8) synthesis (IC₅₀

Clinical studies

In patients with asthma, FP treatment (1 mg twice daily for 2 months) significantly reduced the numbers of mast cells (by 80.2%), eosinophils (by 93.6%), and T cells (CD3, CD4, CD8, CD25; mean reduction of 86.5%) in bronchial biopsy specimens.²⁶ Similarly, the presence of dendritic (CD1a), IgE+, and HLA-DR+ cells in the lamina propria was decreased after FP 1 mg daily for 3 months,²⁷ suggesting attenuation of antigen recognition, processing, and presentation. Finally, FP (500 μg twice daily for

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^☆: From International Medical Affairs, Respiratory, Glaxo Wellcome Research and Development, Middlesex, United Kingdom.

^☆☆: Reprint requests: Malcolm Johnson, PhD, International Medical Affairs, Respiratory, Glaxo Wellcome Research and Development, Stockley Park West, Uxbridge, Middlesex, UK, UB11 1BT.

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Development of fluticasone propionate and comparison with other inhaled corticosteroids☆,☆☆,★

Abstract

Section snippets

Development of fluticasone propionate

Receptor Pharmacology

Anti-inflammatory activity

Clinical studies

Trends Pharmacol Sci

J Biol Chem

Respir Med

J Allergy Clin Immunol

Steroids

Respir Med

Locally active corticosteroids: structure-activity relationships

Synthesis and structure-activity relationships in a series of anti-inflammatory corticosteroid analogues, halomethyl androstane-17β-carbothiates and 17β-carboselenoates

J Med Chem

A bio-assay for the concomitant assessment of the antiphlogistic and thymolytic activities of topically applied corticoids

Endocrinology

Percutaneous absorption of steroids

Arch Dermatol

A comparison of the molecular structures of six corticosteroids

J Am Chem Soc

Dissolution tissue binding and kinetics of receptor binding of inhaled glucocorticoids

Eur Respir J

Efflux of glucocorticoids from human lung tissue to human plasma in vitro

Eur Respir J

Distribution of inhaled fluticasone propionate between lung tissue and blood plasma in vivo

Eur Respir J