Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides

Tucker, Howard; Crook, J. W.; Chesterson, G. J.

doi:10.1021/jm00400a011

Cited by 132 publications

(103 citation statements)

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“…Previous authors suggested that electron-withdrawal properties of the R3 phenyl substituent enhancing the H-bond acceptor capability at the R2 position are important for antagonism (Singh et al 2000;Teutsch et al 1994;Tucker et al 1988). In contrast, the authors of a recent AR homology study counter that the steric/hydrophobic interaction aspects of this substituent are more important components for binding (Marhefka et al 2001), a view more consistent with the present findings.…”

Section: Discussionsupporting

confidence: 91%

“…SAR evidence gathered from previous study of an extensive series of nonsteroidal antiandrogens (Tucker et al 1988), some with both agonist and antagonist properties, is consistent with this view. In that study, more than 70 compounds were synthesized and tested, all 3-(substituted thio)-2-hydroxypropionanilides (HPAs) containing the essential structural moiety illustrated in Figure 2 with an additional polar hydroxyl substituent on X.…”

Section: Discussionsupporting

confidence: 66%

“…For the purposes of qualitative identification of important SAR features and structural elements relative to AR activity, however, we believe that comparisons can be made across diverse data sets provided that one uses only relative information extracted from within those data sets (e.g., in considering the structural features that distinguish agonist from antagonist activity among the HPAs) (Tucker et al 1988). Prior SAR investigations aimed at understanding and optimizing the activity of nonsteroidal antiandrogens contain a wealth of potentially useful information (Singh et al 2000;Teutsch et al 1994;Tucker et al 1988). These data can and should be considered in efforts to generate useful hypotheses and appropriate model constraints for screening of environmental compounds for potential androgenic activity.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative structure-activity relationship (QSAR) models and qualitative SAR approaches have had some success in identifying and depicting structural features that contribute to the ability of a chemical to interact with steroid hormones, for both the estrogen receptor (ER) (Anstead et al 1997;Fang et al 2001;McKinney and Waller 1994;Tong et al 1997aTong et al , 1997bTong et al , 1998Waller et al 1996b;Wiese and Brooks 1994) and the AR (Loughney and Schwender 1992;Mekenyan et al 1997;Singh et al 2000;Tucker et al 1988;Waller et al 1996a). In the case of environmentally occurring chemicals, studies have revealed a common pattern of steric and electronic features involved in molecular recognition and receptor binding affinity, in spite of the molecular diversity of such data sets.…”

mentioning

confidence: 99%

“…Also pertinent to discerning the structural requirements of AR activity are the results of studies aimed at optimizing antiandrogenic function for the design of pharmaceuticals (Singh et al 2000;Teutsch et al 1994;Tucker et al 1988). The essential rules for antiandrogenic function extracted from these studies are a) an electron-deficient aromatic ring with a strong hydrogen bond (H bond) acceptor (e.g., a nitro or cyano); and b) an aryl-amide linkage to a carbon hosting a strong H-bond donor group at the opposite terminus of the ligand (see, e.g., the essential structural moiety depicted in Figure 2).…”

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confidence: 99%

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Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Tamura

Yoshikawa

Gaido

et al. 2003

Environ Health Perspect

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Identification of several environmental chemicals capable of binding to the androgen receptor (AR) and interfering with its normal function has heightened concern about adverse effects across a broad spectrum of environmental chemicals. We previously demonstrated AR antagonist activity of the organophosphate (OP) pesticide fenitrothion. In this study, we characterized AR activity of analogues of fenitrothion to probe the structural requirements for AR activity among related chemicals. AR activity was measured using HepG2 human hepatoma cells transfected with human AR plus an androgen-responsive luciferase reporter gene, MMTV-luc. AR antagonist activity decreased as alkyl chain length of the phosphoester increased, whereas electron-donating properties of phenyl substituents of the tested compounds did not influence AR activity. Oxon derivatives of fenitrothion, which are more likely to undergo hydrolytic degradation, had no detectable AR antagonist activity. Molecular modeling results suggest that hydrogen-bond energies and the maximum achievable interatomic distance between two terminal H-bond capable sites may influence both the potential to interact with the AR and the nature of the interaction (agonist vs. antagonist) within this series of chemicals. This hypothesis is supported by the results of recent AR homology modeling and crystallographic studies relative to agonist- and antagonist-bound AR complexes. The present results are placed in the context of structure-activity knowledge derived from previous modeling studies as well as studies aimed toward designing nonsteroidal antiandrogen pharmaceuticals. Present results extend understanding of the structural requirements for AR activity to a new class of nonsteroidal, environmental, OP-related chemicals.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Tamura

Yoshikawa

Gaido

et al. 2003

Environ Health Perspect

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Novel nonsteroidal inhibitor of cytochrome P45017α (17α-hydroxylase/C17–20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats

Ideyama¹,

Kudoh²,

Tanimoto³

et al. 1998

Prostate

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Male Sex Hormones, Analogs, and Antagonists

Brueggemeier

2010

Burger's Medicinal Chemistry and Drug Discovery

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The steroid testosterone is the major circulating sex hormone of the male and serves as the prototype for the androgens, the anabolic agents, and androgen antagonists. The endogenous androgens are biosynthesized from cholesterol in various tissues in the body; the majority of the circulating androgens are made in the testes under the stimulation of the gonadotropin luteinizing hormone ( LH ). The reduction of testosterone to dihydrotestosterone is necessary for the androgenic actions of testosterone in many androgen target tissues such as the prostate; the oxidation of testosterone by the enzyme aromatase produces estrogens. The androgenic actions of testosterone and dihydrotestosterone are due to their binding to the androgen receptor, followed by nuclear localization, dimerization of the receptor complex, and binding to a specific DNA sequence. This binding of the homodimer to the androgen response element leads to gene expression, stimulation or repression of the synthesis of new mRNA, and subsequent protein biosynthesis. The synthetic androgens and anabolics were prepared to impart oral activity to the androgen molecule, to separate the androgenic effects of testosterone from its anabolic effects, and to improve upon its biological activities. Novel nonsteroidal androgens, termed selective androgen receptor modulators, were developed to impart agonist activity in selective tissues. Drug preparations are used for the treatment of various androgen‐deficient diseases, for the therapy of diseases characterized by muscle wasting and protein catabolism, for postoperative adjuvant therapy, and for the treatment of certain hormone‐dependent cancers. The two major categories of androgen antagonists are the antiandrogens, which block interactions of androgens with the androgen receptor, and the inhibitors of androgen biosynthesis and metabolism. Such compounds have therapeutic potential in the treatment of acne, virilization in women, hyperplasia and neoplasia of the prostate, and baldness and male contraception.

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Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides

Cited by 132 publications

References 0 publications

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Interaction of organophosphate pesticides and related compounds with the androgen receptor.

Novel nonsteroidal inhibitor of cytochrome P45017α (17α-hydroxylase/C17–20 lyase), YM116, decreased prostatic weights by reducing serum concentrations of testosterone and adrenal androgens in rats

Male Sex Hormones, Analogs, and Antagonists

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