共查询到20条相似文献,搜索用时 16 毫秒
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Wenya Han 《Journal of biomolecular structure & dynamics》2020,38(9):2582-2591
AbstractProstate cancer (PCa), an epithelial malignancy that occurs in the prostate, reminds the second leading cause of cancer-related incidence in men worldwidely. Androgen receptor antagonists are the main therapeutic strategy of PCa, which can block the binding of androgen to androgen receptors. However, the long-term treatment of marketed anti-androgens in patients can inevitably cause drug resistance problem. The research of searching for new drugs with novel skeleton is always on the way. Recently, a series of 3-phenylpyrazole derivatives were reported to antagonize the function of AR, but their efficiencies are not good enough and need to be improved. In this work, comparative molecular field analysis and comparative molecular similarity indices analysis methods were employed to study the structure activity relationships of these derivatives. Two different methods were used to obtain the optimal molecular conformation alignments, one is based on atomic alignment and the other is based on molecular docking. The final result shows that both these two strategies can obtain satisfactory results and the atomic alignment performs a little better than docking. The models illustrate the key structural features highly related with the androgenic bioactivity and provide valuable suggestions for the design of new androgen receptor antagonists in future.Communicated by Ramaswamy H. Sarma 相似文献
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Marwah P Marwah A Lardy HA Miyamoto H Chang C 《Bioorganic & medicinal chemistry》2006,14(17):5933-5947
Dehydroepiandrosterone (DHEA), the most abundant steroid in human circulating blood, is metabolized to sex hormones and other C19-steroids. Our previous collaborative study demonstrated that androst-5-ene-3beta,17beta-diol (Adiol) and androst-4-ene-3,17-dione (Adione), metabolites of DHEA, can activate androgen receptor (AR) target genes. Adiol is maintained at a high concentration in prostate cancer tissue; even after androgen deprivation therapy and its androgen activity is not inhibited by the antiandrogens currently used to treat prostate cancer patients. We have synthesized possible metabolites of DHEA and several synthetic analogues and evaluated their role in androgen receptor transactivation to identify AR modulators. Steroids with low androgenic potential in PC-3 cell lines were evaluated for anti-dihydrotestosterone (DHT) and anti-Adiol activity. We discovered three potent antiandrogens: 3beta-acetoxyandrosta-1,5-diene-17-one 17-ethylene ketal (ADEK), androsta-1,4-diene-3,17-dione 17-ethylene ketal (OAK), and 3beta-hydroxyandrosta-5,16-diene (HAD) that antagonized the effects of DHT as well as of Adiol on the growth of LNCaP cells and on the expression of prostate-specific antigen (PSA). In vivo tests of these compounds will reveal their potential as potent antiandrogens for the treatment of prostate cancer. 相似文献
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Ng RA Guan J Alford VC Lanter JC Allan GF Sbriscia T Lundeen SG Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(4):955-958
The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID(50)=0.13mg/day), compared with bicalutamide (ID(50)=0.23mg/day). 相似文献
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Rosaria Gitto Laura De Luca Stefania Ferro Rita Citraro Giovambattista De Sarro Lara Costa Lucia Ciranna Alba Chimirri 《Bioorganic & medicinal chemistry》2009,17(4):1640-1647
A combined ligand-based and structure-based approach has previously allowed us to identify NR2B/NMDA receptor antagonists containing indole scaffold. In order to further explore the main structure activity relationships of this class of derivatives we herein report the design, synthesis and biological evaluation of new analogues. Some derivatives demonstrated to produce significant anticonvulsant properties and NMDA antagonism. The most active of them (3d) showed NR2B binding affinity equipotent to that of ifenprodil. These results were also corroborated by computational studies. 相似文献
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Yamamoto S Matsunaga N Hitaka T Yamada M Hara T Miyazaki J Santou T Kusaka M Yamaoka M Kanzaki N Furuya S Tasaka A Hamamura K Ito M 《Bioorganic & medicinal chemistry》2012,20(1):422-434
A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer. 相似文献
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Ng RA Guan J Alford VC Lanter JC Allan GF Sbriscia T Linton O Lundeen SG Sui Z 《Bioorganic & medicinal chemistry letters》2007,17(3):784-788
The synthesis and in vivo SAR of 5,6-dichloro-benzimidazole derivatives as novel selective androgen receptor antagonists are described. During screening of 2-alkyl benzimidazoles, it was found that a trifluoromethyl group greatly enhances antagonist activity in the prostate. Benzimidazole 1 is a potent AR antagonist in the rat prostate (ID50 = 0.15 mg/day). 相似文献
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Guo C Pairish M Linton A Kephart S Ornelas M Nagata A Burke B Dong L Engebretsen J Fanjul AN 《Bioorganic & medicinal chemistry letters》2012,22(7):2572-2578
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR. 相似文献
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Van Camp JA Hu LY Kostlan C Lefker B Li J Mitchell L Wang Z Yue WS Carroll M Dettling D Du D Pocalyko D Wade K 《Bioorganic & medicinal chemistry letters》2007,17(20):5529-5532
A series of substituted 4-aryl-2-trifluoromethylbenzonitrile analogs were evaluated in the human androgen receptor binding and cellular functional assays. Analogs with sufficient in vitro binding and cellular potency (IC(50)<200 nM) were tested in the progesterone receptor binding assay for selectivity and in the Golden Syrian hamster ear model for in vivo efficacy. Within the series, compound 4 e was identified to be the most active analog in vivo (wax ester inhibition=86%). 相似文献
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Craig D. Boyle Samuel Chackalamannil Lian-Yong Chen Sundeep Dugar Pradeep Pushpavanam William Billard Herbert BinchIII Gordon Crosby Mary Cohen-Williams Vicki L. Coffin Ruth A. Duffy Vilma Ruperto Jean E. Lachowicz 《Bioorganic & medicinal chemistry letters》2000,10(24)
Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition. 相似文献
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M. Walter K. Isensee T. Kottke X. Ligneau J.-C. Camelin J.-C. Schwartz H. Stark 《Bioorganic & medicinal chemistry letters》2010,20(19):5883-5886
With a small series of compounds we demonstrated the variability in the core region of the human histamine H3 receptor (hH3R) antagonist structural blueprint by introducing polar azole groups (oxazole, oxadiazole, thiazole and triazole). Additional variations achieved by coupling different residues to the heterocyclic core structure led to further optimisation of in vitro receptor binding of the novel azole derivatives. 相似文献
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Sexton KE Barrett S Bridgwood K Carroll M Dettling D Du D Fakhoury S Fedij V Hu LY Kostlan C Pocalyko D Raheja N Smith Y Shanmugasundaram V Wade K 《Bioorganic & medicinal chemistry letters》2011,21(18):5230-5233
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds. 相似文献
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Wakabayashi K Miyachi H Hashimoto Y Tanatani A 《Bioorganic & medicinal chemistry》2005,13(8):2837-2846
We designed and synthesized novel pyrrole-2-carboxamide derivatives as androgen antagonists. Compounds 10 and 13 bearing benzylamine or aniline at the 4-position of the pyrrole ring showed moderate androgen antagonistic activity, and inhibited the androgen-dependent growth of Shionogi carcinoma cells (SC-3). Study of the structure-activity relationships of compound 13 led to a potent androgen antagonist 36, which has higher affinity than flutamide (4) for androgen nuclear receptor (AR). Thus, pyrrole-2-carboxamide is a new scaffold for developing AR antagonists. 相似文献
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Yoon J Yoo EA Kim JY Pae AN Rhim H Park WK Kong JY Park Choo HY 《Bioorganic & medicinal chemistry》2008,16(10):5405-5412
Twenty-four compounds of 4-methoxy-N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] benzene sulfonamides and N-[3-(4-substituted phenyl-piperazine-1-yl)propyl] naphthyl sulfonamides were prepared and evaluated as 5-HT(7) receptor antagonists. Most of the compounds showed the IC(50) values of 12-580nM. Four methyl branched analogues were also obtained, but the activity for methyl branched analogues was almost same as its straight chain congeners. Among the synthesized compounds, 3c showed a good activity on 5-HT(7) receptors and a good selectivity on 5-HT(1a), 5-HT(2a), 5-HT(2c), and 5-HT(6) receptors. 相似文献
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Nishikawa-Shimono R Sekiguchi Y Koami T Kawamura M Wakasugi D Watanabe K Wakahara S Matsumoto K Takayama T 《Bioorganic & medicinal chemistry letters》2012,22(9):3305-3310
Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM). 相似文献
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Satoshi Yamamoto Hiromi Kobayashi Tomohiro Kaku Katsuji Aikawa Takahito Hara Masuo Yamaoka Naoyuki Kanzaki Atsushi Hasuoka Atsuo Baba Mitsuhiro Ito 《Bioorganic & medicinal chemistry》2013,21(1):70-83
We designed and synthesized a series of 3-aryl-3-hydroxy-1-phenylpyrrolidine derivatives D and evaluated their potential as novel androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a methyl group at the 2-position (R2) of the pyrrolidine ring increased the AR binding affinity. The (2S,3R) configuration of the pyrrolidine ring was favorable for the AR antagonistic activity. It was found that introduction of an amide substituent (R1) and a pyridin-3-yl group (Q) was effective for reducing the AR agonistic activity which appeared during the optimization of lead compound 6. Compound 54 showed potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft, in which bicalutamide exhibited only partial suppression of tumor growth. Thus, the pyrrolidine derivatives such as 54 are novel AR antagonists, and their properties having efficacy against CRPC are distinct from those of a representative first-generation antagonist, bicalutamide. 相似文献
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Lorna H. Mitchell Lain-Yen Hu Maria Nguyen Stephen Fakhoury Yvonne Smith Donna Iula Catherine Kostlan Matthew Carroll Danielle Dettling Daniel Du David Pocalyko Kimberly Wade Bruce Lefker 《Bioorganic & medicinal chemistry letters》2009,19(8):2176-2178
A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model. 相似文献
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Balog A Salvati ME Shan W Mathur A Leith LW Wei DD Attar RM Geng J Rizzo CA Wang C Krystek SR Tokarski JS Hunt JT Gottardis M Weinmann R 《Bioorganic & medicinal chemistry letters》2004,14(24):6107-6111
A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro. 相似文献
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Toshiyuki Takahashi Yuji Haga Toshihiro Sakamoto Minoru Moriya Osamu Okamoto Katsumasa Nonoshita Takunobu Shibata Takuya Suga Hirobumi Takahashi Tomoko Hirohashi Aya Sakuraba Akira Gomori Hisashi Iwaasa Tomoyuki Ohe Akane Ishihara Yasuyuki Ishii Akio Kanatani Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(13):3511-3516
Continuing medicinal chemistry studies to identify spiropiperidine-derived NPY Y5 receptor antagonists are described. Aryl urea derivatives of a variety of spiropiperidines were tested for their NPY Y5 receptor binding affinities. Of the spiropiperidines so far examined, spiro[3-oxoisobenzofurane-1(3H),4′-piperidine] was a useful scaffold for producing orally active NPY Y5 receptor antagonists. Oral administration of 5c significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 3 mg/kg. In addition, this compound was efficacious in decreasing body weight in diet-induced obese mice. 相似文献