Receptor binding affinity and antiproliferative activity of new antiinflammatory antedrugs: 6-methoxycarbonyl prednisolone and its derivatives

Heiman, Ann S.; Hong, Deasik; Lee, Henry J.

doi:10.1016/0039-128x(94)90121-x

Cited by 11 publications

(5 citation statements)

References 20 publications

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“…Various, mostly prednisolone-based ester derivatives, were synthesized and investigated in a series of attempts designated as "antedrug" designs by H. J. Lee's and coworkers [40,[110][111][112][113][114][115][116][117][118][119]. Unfortunately, the "antedrug" terminology only creates additional confusion.…”

Section: So-called "Antedrug" Steroidsmentioning

confidence: 99%

“…Studied compounds include ester derivatives of steroid 21-oic acids [110], a number of 16α-carboxylate analogues (e.g., 11) [40,[111][112][113]116], 6-carboxylate analogues [114], and (16α,17α-d) isoxazolines derivatives [115,117,118]. Some of these compounds were found to have relatively low activity, similar to that of hydrocortisone or prednisolone, and they also achieved some, but not very significant, improvement in the local-to-systemic activity ratio.…”

Section: So-called "Antedrug" Steroidsmentioning

confidence: 99%

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Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

Bodor¹,

Buchwald²

2006

CPD

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Inhaled and intranasal corticosteroids (ICSs) still are the most effective treatment available for allergic airway diseases and are likely to remain the cornerstone of managing persistent asthma/allergic rhinitis in the foreseeable future. Even if the therapeutic index of this class increased significantly with the introduction of newer corticosteroids, and even if new therapeutic potentials are beginning to emerge with our increasing understanding of the mechanisms of asthma, chronic obstructive pulmonary disease, and rhinitis, corticosteroid development still remains a very important field for drug designers. After a brief review of issues related to the structure-activity relationships of glucocorticoids and the main determinants of their receptor-binding affinity at the glucocorticoid receptor, the main focus of the present article will be on the development of soft corticosteroids, as they are particularly well suited to separate local activity from systemic side effects, which still is an important issue for ICSs. Design consideration required in the search for safe and effective soft drugs on one hand, and safe and effective ICSs on the other hand, will be briefly discussed and illustrated with a number of cases, in particular, with that of loteprednol etabonate and etiprednol dicloacetate, soft corticosteroids that are being developed for a full spectrum of therapeutic applications including asthma and allergic rhinitis.

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Section: So-called "Antedrug" Steroidsmentioning

confidence: 99%

Section: So-called "Antedrug" Steroidsmentioning

confidence: 99%

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

Bodor¹,

Buchwald²

2006

CPD

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“…They were aimed to improve the local-to-systemic activity ratio of antiinflammatory steroids and may be considered as SD designs based on hypothetical inactive metabolites. Studied compounds include ester derivatives of steroid 21-oic acids [53], a number of 16a-carboxylate analogs (e.g., 52) [54,[211][212][213]216,220], 6-carboxylate analogs [214], and (16a,17a-d) isoxazolines derivatives [215,217,218]. Some of these compounds were found to have relatively low activity, similar to that of hydrocortisone or prednisolone, and they also achieved some, but not very significant, improvement in the local-to-systemic activity ratio.…”

Section: Softmentioning

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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“…In a series of attempts aimed to improve the local-to-systemic activity ratio of anti-inflammatory steroids, a variety of mostly prednisolone-based ester derivatives were synthesized and investigated by Lee, Heinman, and coworkers. 18,19,169 -177 The studied compounds include ester derivatives of steroid 21-oic acids, 18 a number of 16␣-carboxylate analogues, 19,169 -171,174 6-carboxylate analogues, 172 and (16␣,17␣-d) isoxazolines derivatives. 173,175,176 It is important to note that, as opposed to the case of loteprednol etabonate, these compounds were not designed based on an existent inactive metabolite of a known drug.…”

Section: Other Steroid Designsmentioning

confidence: 99%

Soft drug design: General principles and recent applications

2000

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Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, β‐blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 58–101, 2000.

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Receptor binding affinity and antiproliferative activity of new antiinflammatory antedrugs: 6-methoxycarbonyl prednisolone and its derivatives

Cited by 11 publications

References 20 publications

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

Corticosteroid Design for the Treatment of Asthma: Structural Insights and the Therapeutic Potential of Soft Corticosteroids

Retrometabolism‐Based Drug Design and Targeting

Soft drug design: General principles and recent applications

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