- Identification of an Orally Bioavailable Chromene-Based Selective Estrogen Receptor Degrader (SERD) That Demonstrates Robust Activity in a Model of Tamoxifen-Resistant Breast Cancer
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About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
- Nagasawa, Johnny,Govek, Steven,Kahraman, Mehmet,Lai, Andiliy,Bonnefous, Celine,Douglas, Karensa,Sensintaffar, John,Lu, Nhin,Lee, Kyoungjin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Maheu, Kate,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
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p. 7917 - 7928
(2018/09/06)
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- TREATMENT OF HOT FLUSHES, VASOMOTOR SYMPTOMS, AND NIGHT SWEATS WITH SEX STEROID PRECURSORS IN COMBINATION WITH SELECTIVE ESTROGEN RECEPTOR MODULATORS
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Novel methods for reduction or elimination of the incidence of hot flushes, vasomotor symptoms, and night sweats while decreasing the risk of acquiring breast, uterine or endometrial cancer and furthermore having beneficial effect by inhibiting the develo
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- TREATMENT OF MALE ANDROGEN DEFICIENCY SYMPTOMS OR DISEASES WITH SEX STEROID PRECURSOR COMBINED WITH SERM
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Novel methods for prevention, reduction or elimination of the incidence of male androgen deficiency symptoms or diseases including male hypogonadism-associated symptoms and diseases associated with low serum testosterone and/or low DHEA or low total andro
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- COMBINATIONS OF BENZOPYRAN COMPOUNDS, COMPOSITIONS AND USES THEREOF
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This invention relates to a method of treating a disorder modulated, mediated or affected by the estrogen receptor in a subject comprising administering to the subject a specific benzopyran (in the form of a mixture of S-C2 and R-C2 diastereomers or its pure S-diastereomer) in combination with an agent selected from the group consisting of an mTOR inhibitor, a CDK 4/6 inhibitor, a PI3 Kinase inhibitor, a taxane, an antimetabolite, and an antitumor antibiotic.
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- SUBSTITUTED BENZOPYRAN COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Benzopyran compounds with anti-estrogenic activity are provided as Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII and XVIII. These compounds are useful for the treatment or prevention of a variety of conditions that are modulated through the estrogen receptor in mammals including humans.
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- NOVEL BENZOPYRAN COMPOUNDS, COMPOSITIONS AND USES THEREOF
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Benzopyran compounds with strong anti-estrogenic activity and essentially no estrogenic activity are provided, which are OP- 1038, which is 3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin-l-yl]ethoxy}phenyl)-2H-chromen-7-ol, and OP-1074, which is (2S)-3-(4-hydroxyphenyl)-4-methyl-2-(4-{2-[(3R)-3-methylpyrrolidin- 1 -yl]ethoxy}phenyl)-2H-chromen-7-ol. OP-1074 is a pure anti-estrogen when tested in the agonist mode and a complete anti-estrogen when tested in the antagonist mode. These compounds are useful for the treatment or prevention of a variety of conditions that are modulated through the estrogen receptor in mammals including humans.
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- Indazoles, benzisoxazoles and benzisothiazoles as estrogenic agents
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The present invention relates to compounds of formula (I): in which R1, R2, R3, X, Y and A are as defined in the specification. The compounds are modulators of the estrogen receptors.
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Page/Page column 23-24
(2008/06/13)
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- 4-fluoroalkyl-2h-benzopyrans anti-estogenic activity
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This invention describes the new 4-fluoroalkyl-2H-benzopyrans of general formula I, in which Z is a straight-chain or branched-chain alkyl group with up to 5 carbon atoms that is fluorinated in at least one place, preferably a trifluoromethyl group, and R1, R2, X, Y and n have the meanings that are indicated in the description. The new compounds have at their disposal strong antiestrogenic action. In addition, they can have at their disposal estrogenic action that occurs in a tissue-selective manner. They can be used for the production of pharmaceutical agents, especially for the treatment of estrogen-dependent diseases and tumors and pharmaceutical agents for hormone replacement therapy (HRT) as well as for the prevention and treatment of osteoporosis.
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- Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
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Novel methods for the medical treatment and/or inhibition of the development of osteoporosis, breast cancer, hypercholesterolemia, hyperlipidemia or atherosclerosis in susceptible warm-blooded animals including humans involving administration of selective
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Page column 31; 34
(2008/06/13)
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- Benzopyran-containing compounds and prodrug forms thereof
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Certain benzopyran antiestrogens are disclosed for treating estrogen sensitive diseases such as breast cancer. Prodrug forms provide ease of manufacturing, good shelf life, and bioavailibility.
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- Enantioselective synthesis
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A short practical commercial process for the efficient enantioselective synthesis of the non-steroidal antiestrogen of formula I or XIV or a pharmaceutically acceptable salt thereof.
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- Structure-Activity Relationship of Antiestrogens. Phenolic Analogues of 2,3-Diaryl-2H-1-benzopyrans
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Phenolic analogues of 2--3-phenyl-2H-1-benzopyran (1), a novel antiestrogen, were synthesized and evaluated for their structure-activity relationship.Incorporation of OH at position 7 was found to improve receptor affinity of
- Sharma, Arun P.,Saeed, Ashraf,Durani, Susheel,Kapil, Randhir S.
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p. 3222 - 3229
(2007/10/02)
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