New steroidal anti-inflammatory antedrugs: Methyl 3,20-dioxo-9α-fluoro-11β,17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11β,17α-dihydroxy-9α-fluoro-1,4-pregnadiene-16α-carboxylate

Heiman, Ann S.; Ko, Dong-Hoon; Chen, Meiqin; Henry, John

doi:10.1016/s0039-128x(97)00020-2

Cited by 19 publications

(24 citation statements)

References 24 publications

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“…The definition of an "antedrug" [53][54][55][56] is essentially the same as that of a soft drug [15,[38][39][40], and it was introduced later. The Latin ante-prefix, which is very similar in meaning to the Greek proprefix (e.g., prior to, precedent), implies the conceptual opposite of a soft drug, that is, an inactive agent that has to be activated by metabolism.…”

Section: Soft Drug Versus Prodrugmentioning

confidence: 99%

“…Compound 51 was found not to degrade in rat or human plasma over 30 min at 37 C, indicating that the C-21 methyl ester, which is sterically strongly hindered in these structures, is stable to plasma esterases under these conditions. "Antedrug" Steroids Various, mostly prednisolone-based ester derivatives, were synthesized and investigated in a series of attempts designated as "antedrug" designs [53,54,[211][212][213][214][215][216][217][218][219]. 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.…”

Section: Softmentioning

confidence: 99%

“…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%

“…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. Relative binding affinities (RBA considering RBA Dex ¼ 100) of two such 9a-fluorinated steroids for the cytosolic glucocorticoid receptor are 11 and 4 for FP16CM (52) and its 21-acetate derivative FP16CMAc, respectively [54,178]. For comparison, loteprednol etabonate (41), a nonfluorinated soft steroid, has a RBA of around 150 [163,178].…”

Section: Softmentioning

confidence: 99%

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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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Section: Soft Drug Versus Prodrugmentioning

confidence: 99%

Section: Softmentioning

confidence: 99%

Section: Softmentioning

confidence: 99%

Section: Softmentioning

confidence: 99%

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Retrometabolism‐Based Drug Design and Targeting

Bodor

Buchwald

2010

Burger's Medicinal Chemistry and Drug Discovery

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“…Typically, experimental GR binding affinities are obtained with rat cytosol preparations by determining the concentration necessary to inhibit by 50% the binding of a given concentration of 3 H-DEX (IC 50 ). Depending on the assay, the binding affinity of DEX itself is usually somewhere in the range of 2-12 nM [38][39][40][41][42].…”

Section: Receptor-binding Affinitymentioning

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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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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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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New steroidal anti-inflammatory antedrugs: Methyl 3,20-dioxo-9α-fluoro-11β,17α,21-trihydroxy-1,4-pregnadiene-16α-carboxylate and methyl 21-acetyloxy-3,20-dioxo-11β,17α-dihydroxy-9α-fluoro-1,4-pregnadiene-16α-carboxylate

Cited by 19 publications

References 24 publications

Retrometabolism‐Based Drug Design and Targeting

Retrometabolism‐Based Drug Design and Targeting

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

Soft drug design: General principles and recent applications

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