Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator

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• 作者：Jiawang Liu ; Shilong Zheng ; Shanchun Guo ; Changde Zhang ; Qiu Zhong ; Qiang Zhang ; Peng Ma ; Elena V. Skripnikova ; Melyssa R. Bratton ; Thomas E. Wiese ; Guangdi Wang
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：102-106
• 全文大小：379K
• ISSN：1948-5875

文摘

Development of orally bioavailable nonsteroidal selective estrogen receptor downregulators (SERDs) provides clinical opportunities for the long-term treatment and adjuvant therapy of breast cancer at all stages. We describe the design, synthesis, and identification of a boron-modified GW7604 derivative (GLL398, 9), a SERD candidate, in which a boronic acid functional group replaces the phenolic hydroxyl group of GW7604. Compound 9 strongly binds to ERα in a fluorescence resonance energy transfer binding assay (IC₅₀ = 1.14 nM) and potently degrades ERα in MCF-7 breast cancer cells (IC₅₀ = 0.21 μM). Most importantly, the introduction of the boronic acid group confers superior oral bioavailability of 9 (AUC = 36.9 μg·h/mL) in rats as compared to GW7604 (AUC = 3.35 μg·h/mL). The strikingly favorable pharmacokinetic property of 9 makes it a promising oral SERD suitable for clinical evaluation.