- Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin
-
We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E:Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.
- Savage, Scott,McClory, Andrew,Zhang, Haiming,Cravillion, Theresa,Lim, Ngiap-Kie,Masui, Colin,Robinson, Sarah J.,Han, Chong,Ochs, Christoph,Rege, Pankaj D.,Gosselin, Francis
-
p. 11571 - 11576
(2018/10/02)
-
- PROCESS FOR THE PREPARATION OF (E)-3-(4-((E)-2-(2-CHLORO-4-FLUOROPHENYL)-1-(1H-INDAZOL-5-YL)BUT-1-EN-1-YL)PHENYL)ACRYLIC ACID
-
Processes are described for the preparation of estrogen receptor modulating compound, (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (I): and salts thereof, and intermediates useful for the preparation of (I).
- -
-
-
- Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts
-
Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
- Lai, Andiliy,Kahraman, Mehmet,Govek, Steven,Nagasawa, Johnny,Bonnefous, Celine,Julien, Jackie,Douglas, Karensa,Sensintaffar, John,Lu, Nhin,Lee, Kyoung-Jin,Aparicio, Anna,Kaufman, Josh,Qian, Jing,Shao, Gang,Prudente, Rene,Moon, Michael J.,Joseph, James D.,Darimont, Beatrice,Brigham, Daniel,Grillot, Kate,Heyman, Richard,Rix, Peter J.,Hager, Jeffrey H.,Smith, Nicholas D.
-
p. 4888 - 4904
(2015/07/02)
-
- ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
-
Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.
- -
-
-