Rational Design of a Boron-Modified Triphenylethylene (GLL398) as an Oral Selective Estrogen Receptor Downregulator.
ACS Med Chem Lett
; 8(1): 102-106, 2017 Jan 12.
Article
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| MEDLINE
| ID: mdl-28105283
ABSTRACT
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.
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MEDLINE
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2017
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Article