100238-42-4Relevant articles and documents
Design and Synthesis of Basic Selective Estrogen Receptor Degraders for Endocrine Therapy Resistant Breast Cancer
Lu, Yunlong,Gutgesell, Lauren M.,Xiong, Rui,Zhao, Jiong,Li, Yangfeng,Rosales, Carlo I.,Hollas, Michael,Shen, Zhengnan,Gordon-Blake, Jesse,Dye, Katherine,Wang, Yueting,Lee, Sue,Chen, Hu,He, Donghong,Dubrovyskyii, Oleksii,Zhao, Huiping,Huang, Fei,Lasek, Amy W.,Tonetti, Debra A.,Thatcher, Gregory R. J.
, p. 11301 - 11323 (2019)
The clinical steroidal selective estrogen receptor (ER) degrader (SERD), fulvestrant, is effective in metastatic breast cancer, but limited by poor pharmacokinetics, prompting the development of orally bioavailable, nonsteroidal SERDs, currently in clinical trials. These trials address local breast cancer as well as peripheral metastases, but patients with brain metastases are generally excluded because of the lack of blood-brain barrier penetration. A novel family of benzothiophene SERDs with a basic amino side arm (B-SERDs) was synthesized. Proteasomal degradation of ERα was induced by B-SERDs that achieved the objectives of oral and brain bioavailability, while maintaining high affinity binding to ERα and both potency and efficacy comparable to fulvestrant in cell lines resistant to endocrine therapy or bearing ESR1 mutations. A novel 3-oxyazetidine side chain was designed, leading to 37d, a B-SERD that caused endocrine-resistant ER+ tumors to regress in a mouse orthotopic xenograft model.
BENZOTHIOPHENE ESTROGEN RECEPTOR MODULATORS
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Paragraph 0629-0630, (2018/08/29)
This invention is a benzothiophene estrogen receptor modulator or its pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof to treat an estrogen-related medical disorder.
Novel SERMs based on 3-aryl-4-aryloxy-2H-chromen-2-one skeleton - A possible way to dual ERα/VEGFR-2 ligands for treatment of breast cancer
Luo, Guoshun,Li, Xinyu,Zhang, Guoqing,Wu, Chengzhe,Tang, Zhengpu,Liu, Linyi,You, Qidong,Xiang, Hua
, p. 252 - 273 (2017/09/25)
There is considerable interest in developing new SERMs as multifunctional agents in women's health. Development of dual selective estrogen receptor modulators/VEGFR-2 inhibitors (SERMs/V-2I) has been an attractive strategy for the discovery of new breast cancer therapeutic agents. Our previous efforts led to the preparation of a series of 3-aryl-4-anilino-2H-chromen-2-ones endowed with potent estrogen receptor binding affinity and anti-proliferative efficacy. In this study, various structurally related 3-aryl-4-anilino/aryloxy-2H-chromen-2-one analogues were rationally designed, synthesized and evaluated as a new chemo-type of dual ERα and VEGFR-2 inhibitors. Most of the derivatives exhibited potent activities in both enzymatic and cellular assays. SAR investigation revealed that introducing of bioisosteric O atom at the C-4 position of coumarin scaffold is beneficial to improve the inhibitory potency, especially in ERα binding affinity assay. Furthermore, most of the piperidyl substituted compounds showed better inhibitory activity against MCF-7 and Ishikawa cells than lead compounds BL-18d, tamoxifen and Vandetanib. Optimization of the hit compound, identified in an ERα binding affinity assay, led to compound 42d, exhibiting an IC50 for ERα binding affinity of 2.19 μM while retaining an excellent inhibition on VGFR-2 as well as a potent suppression on the growth of angiogenesis-related cells. In RT-PCR assay, 42d exerted significantly antiestrogenic property via suppressing the expression of progesterone receptor (PgR) mRNA in MCF-7 cells, which was consistent with the ERα antagonistic property of a selective estrogen receptor modulator. Further mechanism investigation demonstrated that compound 42d could inhibit the activation of VEGFR-2 and subsequent signaling transduction of Raf-1/MAPK/ERK pathway in MCF-7 cells. All these results together with molecular modeling studies open a new avenue for the development of multifunctional agents targeting ERα and VEGFR-2 in the therapy of some breast cancers.
LTA4H modulators and uses thereof
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Page/Page column 30, (2008/12/07)
Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and/or conditions associated with inflammation.
Identification of a potent, selective, and orally active leukotriene A 4 hydrolase inhibitor with anti-inflammatory activity
Grice, Cheryl A.,Tays, Kevin L.,Savall, Brad M.,Wei, Jianmei,Butler, Christopher R.,Axe, Frank U.,Bembenek, Scott D.,Fourie, Anne M.,Dunford, Paul J.,Lundeen, Katherine,Coles, Fawn,Xue, Xiaohua,Riley, Jason P.,Williams, Kacy N.,Karlsson, Lars,Edwards, James P.
experimental part, p. 4150 - 4169 (2009/07/19)
LTA4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA4H stereospecifically catalyzes the transformation of the unstable epoxide LTA4 to the diol LTB4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
Phenyl and pyridyl LTA4H modulators
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Page/Page column 27, (2010/11/24)
Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and inflammatory conditions.
BENZIMIDAZOLE, BENZTHIAZOLE AND BENZOXAZOLE DERIVATIVES AND THEIR USE AS LTA4H MODULATORS
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Page/Page column 82, (2010/02/10)
Leukotriene A4 hydrolase (LTA4H) inhibitors of formula I, compositions containing them, and their use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and/or conditions associated with inflammation, wherein X is selected from the group consisting of NR5, O, and S, with R5 being one of the H and CH3; Y is selected from the group consisting of CH2 and O; R4 is selected from the group consisting of H, OCH3, Cl, F, Br, I, OH, NH2, CN, CF3.
Benzothiophene compounds, intermediates, compositions, and methods
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, (2008/06/13)
The present invention provides intermediate compounds and processes for the preparation of compounds of formula I STR1 wherein R1a is --H or --OR7a in which R7a is --H or a hydroxy protecting group; R2a is --H, halo, or --OR8a in which R8a is --H or a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is --O-- or --S--; or a pharmaceutically acceptable salt thereof.
Benzothiophene compounds, intermediates, compositions, and methods
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, (2008/06/13)
The present invention provides a method for inhibiting endometriosis comprising administering to a woman an effective amount of a compound of formula I STR1 wherein R1a is --H or --OR7a in which R7a is --H or a hydroxy protecting group; R2a is --H, halo, or --OR8a in which R8a is --H or a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is --O-- or --S--; or a pharmaceutically acceptable salt thereof.
Method of treating estrogen dependent cancers
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, (2008/06/13)
A method for alleviating the symptoms of post-menopausal syndrome comprising administering to a woman in need thereof an effective amount of a compound of formula I STR1 wherein R1a is --H or --OR7a in which R7a is --H or a hydroxy protecting group; R2a is --H, halo, or --OR8a in which R8a is --H or a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is --O-- or --S--; or a pharmaceutically acceptable salt thereof.
