阿他美坦(Atamestane) - 药物靶点：aromatase_专利_临床

概要

基本信息

药物类型

小分子化药

别名

BIOMED 777、BIOMED-777、SH 489

+ [3]

靶点

aromatase

作用方式

抑制剂

作用机制

aromatase抑制剂(芳香酶抑制剂)

治疗领域

肿瘤皮肤和肌肉骨骼疾病泌尿生殖系统疾病

在研适应症-

非在研适应症

晚期乳腺癌乳腺癌转移性乳腺癌+ [1]

原研机构

Bayer AG

在研机构-

非在研机构

Intarcia Therapeutics, Inc.Bayer Schering Pharma AG

权益机构-

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C20H26O2

InChIKeyPEPMWUSGRKINHX-TXTPUJOMSA-N

CAS号96301-34-7

关联

5

项与阿他美坦相关的临床试验

NCT00267553

/ Terminated临床3期

Open Label Treatment and Survival Continuation Study of Atamestane Plus Toremifene Versus Letrozole in Advanced Breast Cancer

Protocol 777-CLP-32 is the treatment and survival continuation protocol of Biomed 777-CLP-29, and will continue to compare combined hormonal therapy using the experimental aromatase inhibitor (AI) atamestane combined with the FDA-approved anti-estrogen toremifene (Fareston®), to the single agent FDA-approved aromatase inhibitor letrozole (Femara®) for the treatment of advanced breast cancer. The purpose of this study is to determine whether maximal estrogen suppression achieved via the combination of atamestane, plus toremifene (Fareston®), is more effective than letrozole (Femara®) in delaying the growth of breast cancer.

开始日期2005-11-01

申办/合作机构

Intarcia Therapeutics, Inc.

NCT00097344

/ Terminated临床3期

Phase 3 Study of Atamestane Plus Toremifene Versus Letrozole in Advanced Breast Cancer

The purpose of this study is to determine whether maximal estrogen suppression achieved via the combination of an experimental drug, atamestane, plus an FDA-approved drug, toremifene (Fareston®), is more effective than another approved drug, letrozole (Femara®), in delaying the growth of breast cancer, and whether the side effects of the combined hormonal therapy are different from the side effects of letrozole.

开始日期2004-12-01

申办/合作机构

Intarcia Therapeutics, Inc.

NCT00044291

/ Completed临床3期

Phase III Study of Atamestane Plus Toremifene Versus Letrozole in Advanced Breast Cancer

The purpose of this study is to determine whether the first line combination hormonal therapy of an experimental drug, atamestane, plus an FDA-approved drug, toremifene (Fareston®), is more effective than another approved drug, letrozole (Femara®), in delaying the growth of breast cancer in postmenopausal patients with locally advanced or metastatic breast cancer, and whether the side effects of the combination are different from the side effects of letrozole.

开始日期2002-06-01

申办/合作机构

Intarcia Therapeutics, Inc.

100 项与阿他美坦相关的临床结果

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100 项与阿他美坦相关的转化医学

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100 项与阿他美坦相关的专利（医药）

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53

项与阿他美坦相关的文献（医药）

2020-07-01·Journal of advanced research2区 · 综合性期刊

Whole-cell fungal-mediated structural transformation of anabolic drug metenolone acetate into potent anti-inflammatory metabolites

2区 · 综合性期刊

ArticleOA

作者: Siddiqui, Mahwish ; Wang, Wei ; Atta-Ur-Rahman ; Wang, Yan ; Atia-Tul-Wahab ; Choudhary, M Iqbal ; Jabeen, Almas

Seven new derivatives, 6α-hydroxy-1-methyl-3-oxo-5α-androst-1-en-17-yl acetate (2), 6α,17β-dihydroxy-1-methyl-3-oxo-5α-androst-1-en (3), 7β-hydroxy-1-methyl-3-oxo-5α-androst-1-en-17-yl acetate (4), 15β,20-dihydroxy-1-methyl-3-oxo-5α-androst-1-en-17-yl acetate (5), 15β-hydroxy-1-methyl-3-oxo-5α-androst-1-en-17-yl acetate (6), 12β,17β-dihydroxy-1-methyl-3-oxoandrosta-1,4-dien (11), and 7β,15β,17β-trihydroxy-1-methyl-3-oxo-5α-androst-1-en (14), along with six known metabolites, 17β-hydroxy-1-methyl-3-oxoandrosta-1,4-dien (7), 17β-hydroxy-1-methyl-3-oxo-5α-androst-1-en (8), 17β-hydroxy-1-methyl-3-oxo-5β-androst-1-en (9), 1-methyl-5β-androst-1-en-3,17-dione (10), 1-methyl-3-oxoandrosta-1,4-dien-3,17-dione (12), and 17β-hydroxy-1α-methyl-5α-androstan-3-one (13) of metenolone acetate (1), were synthesized through whole-cell biocatalysis with Rhizopus stolonifer, Aspergillus alliaceous, Fusarium lini, and Cunninghamella elegans. Atamestane (12), an aromatase inhibitor, was synthesized for the first time via F. lini-mediated transformation of 1 as the major product. Hydroxylation, dehydrogenation, and reduction were occurred during biocatalysis. Study indicated that F. lini was able to catalyze dehydrogenation reactions selectively. Structures of compounds 1-14 were determined through NMR, HRFAB-MS, and IR spectroscopic data. Compounds 1-14 were identified as non-cytotoxic against BJ human fibroblast cell line (ATCC CRL-2522). Metabolite 5 (81.0 ± 2.5%) showed a potent activity against TNF-α production, as compared to the substrate 1 (62.5 ± 4.4%). Metabolites 2 (73.4 ± 0.6%), 8 (69.7 ± 1.4%), 10 (73.2 ± 0.3%), 11 (60.1 ± 3.3%), and 12 (71.0 ± 7.2%), also showed a good inhibition of TNF-α production. Compounds 3 (IC₅₀ = 4.4 ± 0.01 µg/mL), and 5 (IC₅₀ = 10.2 ± 0.01 µg/mL) showed a significant activity against T-cell proliferation. Identification of selective inhibitors of TNF-α production, and T-cell proliferation is a step forward towards the development of anti-inflammatory drugs.

2019-10-01·The Lancet. Oncology1区 · 医学

Endocrine treatment versus chemotherapy in postmenopausal women with hormone receptor-positive, HER2-negative, metastatic breast cancer: a systematic review and network meta-analysis

1区 · 医学

Review

作者: Daniele Generali ; Sergio Venturini ; Michelino De Laurentiis ; Grazia Arpino ; Mario Giuliano ; Carla Rognoni ; Antonio Giordano ; Guglielmo Thomas ; Thomas Bachelot ; Sabino De Placido ; Guy Jerusalem ; Pietro De Placido ; Francesco Schettini ; Barbara Pistilli ; Lucia Del Mastro ; Fabio Puglisi ; Massimo Cristofanilli ; Aleix Prat ; Manuela Milani

BACKGROUND:

Although international guidelines support the administration of hormone therapies with or without targeted therapies in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, upfront use of chemotherapy remains common even in the absence of visceral crisis. Because first-line or second-line treatments, or both, based on chemotherapy and on hormone therapy have been scarcely investigated in head-to-head randomised controlled trials, we aimed to compare these two different approaches.

METHODS:

We did a systematic review and network meta-analysis with a systematic literature search on PubMed, Embase, Cochrane Central Register of Clinical Trials, Web of Science, and online archives of the most relevant international oncology conferences. We included all phase 2 and 3 randomised controlled trials investigating chemotherapy with or without targeted therapies and hormone therapies with or without targeted therapies as first-line or second-line treatments, or both, in postmenopausal women with hormone-receptor-positive, HER2-negative metastatic breast cancer, published between Jan 1, 2000, and Dec 31, 2017. Additional recently published randomised controlled trials relevant to the topic were also subsequently added. No language restrictions were adopted for our search. A Bayesian network meta-analysis was done to compare hazard ratios (HRs) for progression-free survival (the primary outcome), and to compare odds ratios (ORs) for the proportion of patients achieving an overall response (the secondary outcome). All treatments were compared to anastrozole and to palbociclib plus letrozole. This study is registered in the Open Science Framework online public database, registration DOI 10.17605/OSF.IO/496VR.

FINDINGS:

We identified 2689 published results and 140 studies (comprising 50 029 patients) were included in the analysis. Palbociclib plus letrozole (HR 0·42; 95% credible interval [CrI] 0·25-0·70), ribociclib plus letrozole (0·43; 0·24-0·77), abemaciclib plus anastrozole or letrozole (0·42; 0·23-0·76), palbociclib plus fulvestrant (0·37; 0·23-0·59), ribociclib plus fulvestrant (0·48; 0·31-0·74), abemaciclib plus fulvestrant (0·44; 0·28-0·70), everolimus plus exemestane (0·42; 0·28-0·67), and, in patients with a PIK3CA mutation, alpelisib plus fulvestrant (0·39; 0·22-0·66), and several chemotherapy-based regimens, including anthracycline and taxane-containing regimens, were associated with better progression-free survival than was anastrozole alone. No chemotherapy or hormone therapy regimen was significantly better than palbociclib plus letrozole for progression-free survival. Paclitaxel plus bevacizumab was the only clinically relevant regimen that was significantly better than palbociclib plus letrozole in terms of the proportion of patients achieving an overall response (OR 8·95; 95% CrI 1·03-76·92).

INTERPRETATION:

In the first-line or second-line setting, CDK4/6 inhibitors plus hormone therapies are better than standard hormone therapies in terms of progression-free survival. Moreover, no chemotherapy regimen with or without targeted therapy is significantly better than CDK4/6 inhibitors plus hormone therapies in terms of progression-free survival. Our data support treatment guideline recommendations involving the new combinations of hormone therapies plus targeted therapies as first-line or second-line treatments, or in both settings, in women with hormone-receptor-positive, HER2-negative metastatic breast cancer.

FUNDING:

None.

2015-04-03·Drug and chemical toxicology4区 · 医学

Evidence for the contribution of non-covalent steroid interactions between DNA and topoisomerase in the genotoxicity of steroids

4区 · 医学

Article

作者: John O. Trent ; Ronald D. Snyder ; Patrick A. Holt ; Jon M. Maguire

Fifty two steroids and 9 Vitamin D analogs were docked into ten crystallographically-defined DNA dinucleotide sites and two human topoisomerase II ATP binding sites using two computational programs, Autodock and Surflex. It is shown that both steroids and Vitamin D analogs exhibit a propensity for non-covalent intercalative binding to DNA. A higher predicted binding affinity was found, however, for steroids and the ATP binding site of topoisomerase; in fact these drugs exhibited among the highest topo II binding observed in over 1370 docked drugs. These findings along with genotoxicity data from 26 additional steroids not subjected to docking analysis, support a mechanism wherein the long known, but poorly understood, clastogenicity of steroids may be attributable to inhibition of topoisomerase. A "proof of principle" experiment with dexamethasone demonstrated this to be the likely mechanism of clastogenicity of, at least, this steroid. The generality of this proposed mechanism of genotoxicity across the steroids and vitamin-D analogs is discussed.

100 项与阿他美坦相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	阿他美坦	-	DB12194

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
晚期乳腺癌	临床3期	美国	Intarcia Therapeutics, Inc.	2002-06-01
晚期乳腺癌	临床3期	加拿大	Intarcia Therapeutics, Inc.	2002-06-01
晚期乳腺癌	临床3期	俄罗斯	Intarcia Therapeutics, Inc.	2002-06-01
晚期乳腺癌	临床3期	乌克兰	Intarcia Therapeutics, Inc.	2002-06-01
转移性乳腺癌	临床3期	美国	Intarcia Therapeutics, Inc.	2000-10-01
乳腺癌	临床2期	德国	Bayer Schering Pharma AG	1999-01-01
前列腺增生症	临床2期	欧洲	Bayer Schering Pharma AG	1996-11-01

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2006	临床3期	晚期乳腺癌一线	865	Atamestane 500 mg per day + Toremifene 60 mg per day	憲淵艱繭餘衊廠製糧艱(鏇鬱獵壓繭醖積網築廠) = 願鹹廠範餘選鏇積鏇顧鏇鹹選築餘鏇遞淵糧鬱 (構選窪繭繭艱觸餘壓鬱 )	-	2006-06-20
				Letrozole 2.5 mg per day	憲淵艱繭餘衊廠製糧艱(鏇鬱獵壓繭醖積網築廠) = 築窪鹹廠夢淵製積壓築鏇鹹選築餘鏇遞淵糧鬱 (構選窪繭繭艱觸餘壓鬱 )