Synthesis and adrenergic .beta.-blocking activity of some 1,3-benzodioxole derivatives

Tatsuno, Hideko; Goto, Katsutoshi; Shigenobu, Koki; Kasuya, Yutaka; Obase, Hiroyuki; Yamada, Yoshiuki; Kudo, Shiro

doi:10.1021/jm00213a015

Cited by 14 publications

(7 citation statements)

References 8 publications

(11 reference statements)

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“…The compound is a potent fl-adrenergic blocker, with an activity approximately the same as that for the corresponding class (I) derivative (III) (Tatsuno, Goto, Shigenobu, Kasuya, Obase, Yamada & Kudo, 1977).…”

mentioning

confidence: 83%

Structure of 2-hydroxy-3-isopropylaminopropyl 3,4-methylenedioxybenzoate hydrochloride

Ammon¹,

El‐Sayed²,

Prasad³

et al. 1986

Acta Crystallogr C

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mentioning

confidence: 83%

Structure of 2-hydroxy-3-isopropylaminopropyl 3,4-methylenedioxybenzoate hydrochloride

Ammon¹,

El‐Sayed²,

Prasad³

et al. 1986

Acta Crystallogr C

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“…These compounds are ester-containing structural analogs of amphiphilic quaternary ammonium compounds, which, similar to cetylpyridinium (108), are surface active substances known for their membrane-disruptive and antimicrobial activities. Contrary to the design of 111, however, hydrolysis here is not followed by additional, fast degradation, but results in well-investigated and common compounds, such as choline (119), betaine (122), and fatty acids (118) (Fig. 27).…”

Section: Environmental-friendly Quaternary Analogsmentioning

confidence: 99%

“…Esmolol Esmolol (BreviblocÔ, 17) is an ultrashort-acting b-blocker also designed to rely on rapidmetabolismbyserumesterases [117,118]. By the late 1970s, it was already known that insertion of an ester moiety between the aromatic ring and the b-amino alcohol side chain [119] or at the more remote para position [120] might not affect b-blocking activity significantly. It was also shown that the acid metabolites 14 (n ¼ 0, 1) are devoid of b-adrenoceptor activity [102,120].…”

Section: Inactive Metabolite-based Soft Drugsmentioning

confidence: 99%

“…Because relatively early in the study of bblockers, it was found that insertion of an ester moiety between the aromatic ring and the bamino alcohol side chain preserves reasonable b-blocking activity [119,123], a variety of such structures have also been synthesized and investigated. Half-lives in blood and liver suggested that ester hydrolysis is the major pathway for the inactivation of these [(arylcarbonyl)-oxy]propanolamines.…”

Section: Inactive Metabolite-based Soft Drugsmentioning

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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“…It was designed by researchers at American Critical Care (McGaw Park, IL). 96 -97 In the late 1970s, it was already noticed that insertion of an ester moiety between the aromatic ring and the ␤-amino alcohol side chain 98 or at the more remote para position 99 might not affect significantly ␤-adrenergic blocking activity. It was also shown that the acid metabolites formed by hydrolysis of 45 (n ϭ 0, 1) are devoid of ␤-adrenoceptor activity.…”

Section: B Soft B-blockersmentioning

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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Synthesis and adrenergic .beta.-blocking activity of some 1,3-benzodioxole derivatives

Cited by 14 publications

References 8 publications

Structure of 2-hydroxy-3-isopropylaminopropyl 3,4-methylenedioxybenzoate hydrochloride

Structure of 2-hydroxy-3-isopropylaminopropyl 3,4-methylenedioxybenzoate hydrochloride

Retrometabolism‐Based Drug Design and Targeting

Soft drug design: General principles and recent applications

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