Recent advances in retrometabolic design approaches

Bodor, Nicholas

doi:10.1016/s0168-3659(99)00040-1

Cited by 15 publications

(10 citation statements)

References 80 publications

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“…Pharmacokinetics can be altered by using the "inactive metabolite approach" 26,27,28 in which one can design a soft analog of a drug that is active at the site of action but undergoes a one-step predicted metabolism in the circulation and will be transformed to the inactive metabolite from which its creation had been started 29 . This process happens after the drug achieves its therapeutic role at the site of action and thus prevents the rest of the body to be exposed to the active drug or to various active or reactive metabolic products.…”

Section: Toxicity Of Glucocorticoidsmentioning

confidence: 99%

Untitled

2012

IJPSR

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Glucocorticosteroids (GCs) are commonly used for long-term medication in immunosuppressive and anti-inflammatory therapy, but prolonged use of GCs produce number of systemic side effects. To further improve the therapeutic index, that is the ratio of the toxic to the therapeutic dose of a drug, it is at least theoretically possible by changing both pharmacokinetics and pharmacodynamic parameters. Pharmacokinetics can deliberately be altered by using the "inactive metabolite approach" in which one can design a soft analog of a drug that is active at the site of action (e.g.,in the lung in case of inhaled medications) but undergoes a one-step predicted metabolism in the circulation and will be transformed to the very inactive metabolite from which its creation had been started. This process happens after the drug achieves its therapeutic role at the site of action and thus prevents the rest of the body to be exposed to the active drug or to various active or reactive metabolic products. Pharmacodynamic possibility to separate beneficial and deleterious effects of steroids is to try to dissociate the two main activities of glucocorticoids, which are transactivation and transrepression.

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Section: Toxicity Of Glucocorticoidsmentioning

confidence: 99%

Untitled

2012

IJPSR

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“…Beside ciclesonide [124], the socalled soft-steroids might represent a new direction in the development of novel steroids. Loteprednol is the first representative of this new drug class synthesized by using the retrometabolic design [125,126]. It has been approved for the treatment of conjunctivitis and uveitis in the United States.…”

Section: Possible Targets In the Cell Nucleusmentioning

confidence: 99%

Asthma therapy in the new millennium

Pahl¹,

Szelenyi²

2002

Inflamm. res.

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Bronchial asthma is one of the most common chronic diseases in modern society and yet, despite the availability of highly effective drugs, there is increasing evidence to suggest that its incidence is increasing. It is a general health problem in several industrialised countries and will remain one for the next decades. With regard to asthma pathogenesis, our understanding has increased tremendously over the last two decades. Therefore, the potential for specific targeted and constructed therapies has become evident. Monoclonal antibodies to IgE, soluble receptors or antibodies to certain cytokines such as IL-4 and IL-5 are being investigated as possible treatments for asthma. Besides the already known receptor antagonists, new compounds directed to novel receptor types (e.g. cytokine, adenosine, adhesion molecules, etc.) are now under development. New targets in the cytosol will come into focus. Preliminary studies of selective phosphodiesterase (PDE) inhibitors in asthmatic patients have been encouraging. It is also very likely that the use of glucocorticoids cannot be excluded from therapy. However, we should generate new glucocorticoids with less side-effects, probably by using the so-called retrometabolic drug design. The first representative of this new steroid class, loteprednol is already approved for the therapy of certain allergic disorders. Because asthma is a disease of many different gene polymorphisms, gene therapy seems to be of low success at present. Alternatively, antisense oligonucleotides could be used. Future developments may also include strategies targeting the remodeling of structural elements of the airways. Today's intensive search for new treatments should ensure a greater diversity of therapeutic possibilities for the management of asthma in the next millennium.

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“…Under physiological conditions, the new drug is converted to an inactive metabolite(s) after it produces a local therapeutic effect. 18,24,25 LE is derived from D 1 -cortienic acid, an inactive metabolite of prednisolone, and unlike other corticosteroids, it has a chloromethyl ester at the carbon-20 position instead of a ketone group (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%