PropionateFluticasone propionate is a trifluorinated glucocorticoid receptor ligand that has been extensively used as an inhaled pharmaceutical for the treatment of asthma. Progress in Medicinal Chemistry, Steven Swallow, in Progress in Medicinal Chemistry Fluticasone propionate is a trifluorinated glucocorticoid receptor propionate group that has been extensively used as an inhaled pharmaceutical for the treatment propionate group asthma Figure The impacts of fluorine on the development of this compound are severalfold as discussed below and build on many years of research in the steroid field.
Sodium propionate - Wikipedia
Fluticasone propionate is a trifluorinated glucocorticoid receptor ligand that has been extensively used as an inhaled pharmaceutical for the treatment of asthma. Progress in Medicinal Chemistry, Steven Swallow, in Progress in Medicinal Chemistry , Fluticasone propionate is a trifluorinated glucocorticoid receptor ligand that has been extensively used as an inhaled pharmaceutical for the treatment of asthma Figure The impacts of fluorine on the development of this compound are severalfold as discussed below and build on many years of research in the steroid field.
The utility of fluorine in the discovery of glucocorticoids has a long history and compounds, such as dexamethasone, registered in the late s were among the first fluorine-containing pharmaceuticals to be marketed.
The early development of such compounds was based on improving the properties of the natural steroid cortisol Figure 63 , specifically attempting to increase its topical potency while removing undesired effects through improving selectivity. The increase in potency, typically measured in in vivo systems, was achieved by one of several approaches: Although anti-inflammatory potency was increased through these changes, undesired mineralocorticoid activity was increased to an even greater extent.
However, this latter activity could be attenuated with substitutions in the position as exemplified in the structure of dexamethasone Figure It was subsequently found that masked alcohols at the and positions were preferred giving rise to, for example, fluocinolone 16,acetonide.
Inhalation to provide topical delivery of such masked compounds, to further minimize the systemic side effects for the treatment of airway disease, led to compounds such as beclomethasone dipropionate that proved to be of value in the treatment of bronchial asthma and rhinitis.
A wide range of analogues were tested using a combination of assays to assess their potential relative to fluocinolone acetonide . A vasoconstriction assay based on topical administration to the skin of human volunteers was used to assess anti-inflammatory activity and tissue penetration, and anti-inflammatory activity was further assessed in a topical rat model that allowed simultaneous assessment of systemic exposure on the undesired hypothalamic—pituitary—adrenal HPA function.
Some key compounds are highlighted in Figure 65 with potencies referenced to fluocinolone acetonide. In particular, introduction of fluorine in the thioester has a profound 8-fold impact on the vasoconstriction potency relative to the desfluoro compound This compound, fluticasone proprionate, has an improved therapeutic index over fluocinolone acetonide.
The lack of effect on HPA function has been ascribed to the potential for metabolic inactivation, and comparison of HPA effects following oral and subcutaneous dosing seemed to confirm this hypothesis, with high first-pass turnover to the acid being observed in rats and zero bioavailability being subsequently observed in man . The weak glucocorticoid activity after oral administration is particularly valuable in the treatment of airway disease where a high proportion of the inhaled dose is swallowed.
The structure of dexamethasone bound the glucocorticoid receptor is illustrated in Figure A structural understanding of the contribution to binding of the fluorine in the fluoromethylthio group seems less clear, though favourable electrostatic interactions with an asparagine residue have been suggested and inductive effects on the polarity of the thioester should also not be ignored .
Davies, in Side Effects of Drugs Annual , Combination therapy produced a statistically significant small improvement in lung function and symptoms but no significant reduction in exacerbations.
There were no significant differences in hoarseness, oral candidiasis, upper respiratory tract infections or headache. The addition of a LABA to an inhaled glucocorticoid resulted in significantly better asthma control than maintenance inhaled glucocorticoids. Headache and withdrawals caused by adverse events were similar.
The authors concluded that the greatest benefit and least harm from using LABAs resulted from their addition to a similar dose of an inhaled glucocorticoid in adults with symptomatic asthma. Bryony Coupe 1 , Kuhn, in Side Effects of Drugs Annual , The incidences and types of adverse events were similar in the two groups. There were no deaths and only a few patients reported serious adverse events. The role of two-combination inhaler therapy was tested in humans exposed to SM.
Either fluticasone propionate and salmetrol or beclomethasone and salbutamol were given. Inhaled corticosteroids and long-acting beta 2-agonists are effective in the treatment of patients with chronic bronchiolitis following exposure to SM.
Persistent cough is a usual occurrence in SM-exposed victims which is alleviated with an anti-tussive. The volume was then made up to the mark using same solvent. The resultant solution was filtered through 0. The software was UVPC personal spectroscopy software version 3. At least five different inhaled corticosteroids are available to treat inflammatory lung diseases in humans: Therapeutic effects are measurable within 24 hours of administration.
Also, these studies were conducted using CFC as propellant for beclomethasone dipropionate. Because aerosolized particles of beclomethasone generated with HFA propellant have a lower MMAD, we can estimate that the dose needed to achieve the same effect in RAO-affected horses would be approximately half of the dose needed with CFC-propelled beclomethasone.
Future clinical trials would be required to determine if these estimated dosages can be confirmed. Therefore, lung deposition in horses would be expected to be similar regardless of the type of propellant used as demonstrated in humans. Comparison of drug efficacies in the treatment of RAO suggest that fluticasone is approximately twice as potent as beclomethasone but currently available pMDI contain beclomethasone HFA that requires approximately twice less drug to achieve the same effect.
Therefore, beclomethasone and fluticasone pMDI should be considered equipotent with currently available formulations. About one-fifth of the currently marketed pharmaceuticals are organofluorine compounds. Some of the top-selling drugs such as atorvastatin, Crestor, efavirenz, fluoxetine, Ciprobay, fluticasone propionate , Faslodex, ezetimibe, Celebrex, and sitagliptin consist of a fluoroaryl moiety, a gem -difluoromethylene moiety, or a trifluoromethyl moiety.
Fluoxetine, a serotonin reuptake inhibitor is a widely used antidepressant drug. Fluorinated drugs such as atorvastatin and ezetimibe are among the top-selling antihypercholesterolemia drugs. Antibacterials, such as flurithromycin have enhanced bioavailability and metabolic stability due to the presence of a fluorine substituent at the metabolically vulnerable site.
Mefloquine, a trifluoromethyl-substituted quinine analog, is one of the most successful drugs for treating malaria. This chapter outlines the synthesis and mechanisms of action of fluorinated drugs focusing on the widely used therapeutics, which include antibacterials, antimalarials, antidiabetics, antiinflammatory agents, antihypercholesterolemia drugs, and antiviral drugs.
The absence of candidiasis with fluticasone propionate group raises some doubts about the accuracy of the safety assessments, as safety was not the primary study end point. Despite obvious synergistic therapeutic effects between salmeterol and fluticasone propionate , concerns about the development of tolerance to the bronchoprotective effect of salmeterol remain. However, tolerance to the bronchoprotective effect of salmeterol against allergen challenge may not be homogeneously distributed in the asthmatic population.
Another controversy is fixed-dose versus adjustable maintenance dosing with combination antiasthmatic drug treatment. While the incidence of asthma exacerbations was significantly lower in the fixed-dose group, drug-related adverse effects were similar 6.
Probably a minimum daily amount of maintenance therapy is necessary to prevent asthma exacerbations in adults. Overall safety was similar in the two groups, but voice alterations were more frequent with the DPI 2. Candidiasis was not reported in either group. There were no signs of impaired adrenal function. Cookies are used by this site. For more information, visit the cookies page. Fluticasone propionate Fluticasone propionate is a trifluorinated glucocorticoid receptor ligand that has been extensively used as an inhaled pharmaceutical for the treatment of asthma.
Progress in Medicinal Chemistry, Related terms: Drugs acting on the respiratory tract M. Salmeterol Xinafoate Manal M. Inflammatory diseases of the lower airway of athletic horses Laurent L. Prakash Reddy, in Organofluorine Compounds in Biology and Medicine , Abstract About one-fifth of the currently marketed pharmaceuticals are organofluorine compounds.
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