Soft drugs. 3. A new class of anticholinergic agents

Bodor, Nicholas; Woods, Ross; Raper, C.; Kearney, Pauline; Kaminski, James J.

doi:10.1021/jm00179a002

Cited by 71 publications

(35 citation statements)

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“…One of the most recent approaches to produce an effective but safe drug is the so-called retrometabolic drug design. Retrometabolically designed drug candidates have already been under investigation in widely different pharmacological fields intended to use as antiglaucoma agents (Bodor, 1989), antimicrobials (Bodor et al, 1980a), antitumor compounds (Bodor and Kaminski, 1980), or as short-acting anticholinergics (Bodor et al, 1980b). As the site of intended action and the site of administration coincide in inhalation therapy, the potential for the application of the retrometabolic approach in the treatment of asthma with ICS is especially promising.…”

Section: Discussionmentioning

confidence: 99%

Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)

Kurucz¹,

Tóth²,

Németh³

et al. 2003

J Pharmacol Exp Ther

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In the present study, the pharmacological effects of etiprednol dicloacetate (BNP-166; ethyl-17␣-dichloroacetoxy-11␤-hydroxyandrosta-1,4-diene-3-one-17␤-carboxylate), a new soft steroid, intended to use for the treatment of asthma, were investigated in an animal model of allergen sensitized and challenged Brown Norway rats using local treatment. The examinations involved the determination of the effect of the compound on the extent of allergen induced broncho-alveolar fluid and lung tissue eosinophilia, goblet cell hyperplasia and mucus production, perivascular edema formation, and airways hyperresponsiveness. The activity of etiprednol dicloacetate was compared with that of budesonide. Using in vitro methods, the soft character of etiprednol dicloacetate was investigated together with its capability to dissociate transrepressing and transactivating properties. We found that combining all the examined parameters etiprednol dicloacetate was at least equipotent with budesonide in the animal model, but in several investigated variables it surpassed the activity of budesonide. The effect of etiprednol dicloacetate in vitro was shown to be the function of the quantity of the serum, present in the assay, it was also strongly affected by the incubation time and decreased significantly when it was preincubated with human plasma. These features are characteristics of a soft drug that is quickly inactivated in the systemic circulation. In addition, it was revealed that while the transrepressing potential of etiprednol dicloacetate remained high, its transactivating activity was greatly reduced. These data indicate that the strong local effect of the compound will very likely be accompanied with a significantly reduced systemic activity predicting favorable selectivity in the pharmacological action of etiprednol dicloacetate.

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Section: Discussionmentioning

confidence: 99%

Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)

Kurucz¹,

Tóth²,

Németh³

et al. 2003

J Pharmacol Exp Ther

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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%

“…The soft drug terminology was originally introduced in 1976 [15,[38][39][40] to contrast Ari€ ens's theoretical drug design concept of nonmetabolizable, hard drugs. Hard drugs do not undergo any metabolism and, hence, avoid the problems caused by reactive intermediates or active metabolites.…”

Section: Soft Drug Versus Hard Drugmentioning

confidence: 99%

“…24), which will be discussed here, were obtained by using methylatropine (96) [ [269][270][271][272][273][274], N-methylscopolamine (97) [275,276], or glycopyrrolate (99) [277] as lead. The soft analog class (106), which will be discussed in the following section, contains soft quaternary analogs [40,278].…”

Section: Soft Estrogensmentioning

confidence: 99%

“…The soft drug concept was first introduced in 1976 [15] and reiterated in 1980 [38][39][40]. Since then, a total of five major SD approaches have been identified [16,17,20,21,24,25,27]:…”

Section: Soft Drug Approachesmentioning

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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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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Soft drugs. 3. A new class of anticholinergic agents

Cited by 71 publications

References 0 publications

Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)

Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)

Retrometabolism‐Based Drug Design and Targeting

Soft drug design: General principles and recent applications

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