Anti-Androgens with full antagonistic activity toward human prostate tumor LNCaP cells with mutated androgen receptor

Ishioka, Toshiyasu; Tanatani, Aya; Nagasawa, Kazuo; Hashimoto, Yuichi

doi:10.1016/s0960-894x(03)00575-4

Cited by 96 publications

(60 citation statements)

References 15 publications

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“…The AR ligand specificity becomes modulated and broadened so that the receptor now can be activated by nonandrogenic molecules including androgen antagonists, corticosteroids, and 17␤-estradiol (E 2 ). For example, the AR mutant T877A, isolated from patients with advanced-stage prostate cancer, is activated not only by androgens, the normal ligands, but also by antiandrogens, such as hydroxyflutamide [HF (22,23)]. Another AR mutant, L701H, has been reported to significantly decrease androgen response but significantly potentiate the responses by glucocorticoids (24).…”

Section: Ar and Prostate Cancermentioning

confidence: 99%

Androgen Receptor Coregulators in Prostate Cancer

Rahman

Miyamoto

Chang

2004

Clinical Cancer Research

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Section: Ar and Prostate Cancermentioning

confidence: 99%

Androgen Receptor Coregulators in Prostate Cancer

Rahman

Miyamoto

Chang

2004

Clinical Cancer Research

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“…Treatment of 14 with 4-fluorophenyl isocyanate provided the urea derivative (22). Reduction of the carbonyl group of 20 with sodium borohydride gave the corresponding secondary alcohol analogue (23).…”

Section: Chemistrymentioning

confidence: 99%

“…Cyproterone acetate (1), which is classified as a steroidal AR antagonist, possesses progestational activity and suppresses the secretion of gonadotrophins, both of which are unwanted side effects. A number of nonsteroidal AR antagonists have been reported in the literature [23][24][25][26][27][28][29][30] and three of these, flutamide (2), nilutamide (3), and bicalutamide (4), are used clinically in conjunction with gonadotropin-releasing hormone (GnRH) agonists. 31) These nonsteroidal AR antagonists exhibit some adverse effects such as mastodynia, gynaecomastia and hepatotoxicity [15][16][17][18][19][20][21][22] ; therefore potent AR antagonists with less adverse effects are highly desirable.…”

mentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of Novel Arylpiperazine Derivatives as Nonsteroidal Androgen Receptor Antagonists

Kinoyama¹,

Taniguchi²,

Yoden³

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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The androgen receptor (AR) is a member of the nuclear receptor superfamily and acts as a ligand-dependent intracellular transcription factor. [1][2][3] The AR is also responsible for mediating the physiological actions of the androgens, namely testosterone and 5a-dihydrotestosterone (DHT). Androgens play a critical role in normal male development and the subsequent maintenance of secondary male characteristics such as muscle mass, bone mass, strength, fat distribution, and spermatogenesis. [4][5][6] The male sexual accessory organs, such as the prostate, are stimulated to grow and are maintained in size and secretory function by the continued actions of androgens. It is well established that androgens play a major role in human prostate disorders. 7) Thus compounds that block the action or synthesis of androgens have been proven useful in the treatment of diseases such as prostate cancer, benign prostatic hypertrophy, hirsutism, and acne. [8][9][10][11] AR antagonists, 12,13) including cyproterone acetate (1), 14) flutamide (2), [15][16][17] nilutamide (3), 18) and bicalutamide (4), [19][20][21][22] have been used clinically for the treatment of prostate cancer (Fig. 1). Cyproterone acetate (1), which is classified as a steroidal AR antagonist, possesses progestational activity and suppresses the secretion of gonadotrophins, both of which are unwanted side effects. A number of nonsteroidal AR antagonists have been reported in the literature [23][24][25][26][27][28][29][30] and three of these, flutamide (2), nilutamide (3), and bicalutamide (4), are used clinically in conjunction with gonadotropin-releasing hormone (GnRH) agonists. 31) These nonsteroidal AR antagonists exhibit some adverse effects such as mastodynia, gynaecomastia and hepatotoxicity [15][16][17][18][19][20][21][22] ; therefore potent AR antagonists with less adverse effects are highly desirable.To identify novel AR antagonists, we conducted an HTS of the Yamanouchi chemical library using a reporter assay, which measured the inhibitory activity of test compounds on androgen-induced activation of AR. Compound 5 was discovered as an HTS hit with an associated IC 50 value of 3.1 mM. Through optimization of the lead compound (5), we have found a series of novel arylpiperazine derivatives. Herein, we describe the results of our studies on the syntheses and structure-activity relationships of these arylpiperazine derivatives as novel nonsteroidal AR antagonists. ChemistryCompounds selected for biological evaluation were * To whom correspondence should be addressed. Research, Yamanouchi Pharmaceutical Co., Ltd.; 21 Miyukigaoka, Tsukuba, Japan: and b Institute for Technology Development, Yamanouchi Pharmaceutical Co., Ltd.; 3-17-1 Hasune, Itabashi-ku, Tokyo 174-8612, Japan. Received July 30, 2004; accepted August 30, 2004;

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“…Therefore, the search for new antiandrogenic agents that exhibit no agonistic activities, socalled "AR pure antagonists," has been conducted. 9,10) We previously reported that some steroidal compounds that have a side chain at the position 7a such as compound 4, exhibited AR pure antagonistic activities in reporter gene assay (RGA) (Chart 1). 11,12) Since the steroidal core structures have intrinsic agonistic activities, the side chains are critical for pure antagonistic activities.…”

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confidence: 99%

Discovery of an Orally-Active Nonsteroidal Androgen Receptor Pure Antagonist and the Structure-Activity Relationships of Its Derivatives

Tachibana

Imaoka

Shiraishi

et al. 2008

CHEMICAL & PHARMACEUTICAL BULLETIN

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The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC 50 ‫031؍‬ nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED 50 ‫؍‬ 7 mg/kg).Key words androgen receptor; pure antagonist; prostate cancer Chem. Pharm. Bull. 56(11) 1555-1561 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: tachibanakzt@chugai-pharm.co.jp Chart 1. Structures of AR AntagonistsIn the preparation of aminonitriles 8a-l by the coupling of corresponding amines 7 with acetone cyanohydrin 6, NEt 3 was used when the amine was HCl salt (Chart 2). Isothiocyanate 10, which was derived from 9 and thiophosgene, was coupled with compounds 8a-l in THF in the presence of NEt 3 under reflux to give 5-imino-2-thioxoimidazolidines 11a-h and 14a-d. The imino groups and terminal esters of compounds 11a-h were hydrolyzed successively to give methylene linker compounds 13a-h (Chart 3). Compound 14a, in which the protecting group of phenolic OH was the methoxymethyl group, was converted to phenol-terminal thiohydantoin 16a directly by heating in 6 N-HCl and dioxane. Compounds 14b-d, in which the hydroxyl groups were protected by the methyl group, were converted to compounds 15a-c under the same conditions followed by deprotection of the methyl group by BBr 3 . Alkylation of the hydroxyl groups of 16a-d followed by hydrolysis of the terminal esters gave phenyl-inserted derivatives 18a-d (Chart 4).The synthesized compounds were evaluated for their in vitro binding affinities and agonist/antagonist activities for AR using the same procedures as reported previously.11) The binding affinity for AR was determined by displacement of [ 3 H]-mibolerone with the test compound utilizing CHO-K1/hAR cells. The agonistic and antagonistic activities of the compounds for AR were determined by RGA using hARtransfected Hela cells. Antagonistic activity was determined by the IC 50 value, the concentration of a compound that inhibits the transcriptional activity of 0.1 nM of DHT by 50%.To determine agonistic activity, we calculated the value of EC 5 , the concentration of a compound-treated group in which the transcriptional activity is 5% of the transcriptional activity of 0.1 nM of DHT. The maximum transcriptional activity of each compound indicated as its efficacy (% of 0.1 nM of DHT). A "pure antagonist" was defined as having an EC 5 value greater than 10000 nM. First, we evaluated RU56187 (5) for its binding and transcriptional activities for AR in our assay systems to estimate the validity of the compound as a template (Table 1, Fig. 1). As shown in Fig. 1, it exhibited remarkable agonistic activity at concentration as low as 1 nM. Although it tended to show antagonistic activities at lower concentrations, its own agon...

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Anti-Androgens with full antagonistic activity toward human prostate tumor LNCaP cells with mutated androgen receptor

Cited by 96 publications

References 15 publications

Androgen Receptor Coregulators in Prostate Cancer

Androgen Receptor Coregulators in Prostate Cancer

Synthesis and Pharmacological Evaluation of Novel Arylpiperazine Derivatives as Nonsteroidal Androgen Receptor Antagonists

Discovery of an Orally-Active Nonsteroidal Androgen Receptor Pure Antagonist and the Structure-Activity Relationships of Its Derivatives

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