Boronic acid has been proved a bioisostere of a phenolic hydroxyl group with superior pharmacokinetic properties. Using this knowledge, we have identified an orally bioavailable steroidal SERD fulvestrant-3 boronic acid (ZB716). Herein, we report the modification of GW7604, a non-steroidal estrogen receptor downregulator, forming a boronated GW7604 (GLL398). It possesses quite a high affinity to ERα in a fluorescence resonance energy transfer binding assay with an IC<sub>50</sub> of 1.14 nM, which is 10-fold stronger than GW7604 does. Estrogen receptor reporter gene luciferase assay suggests that GLL398 is an antiestrogen against 17β-estrodiol. <i>In vitro </i>cell assays show that GLL398 exhibits comparable potencies as GW7604 in inhibiting breast cancer cell proliferation and degrading ERα protein. Most importantly, GLL398 confers superior oral bioavailability (AUC = 36.9 μg×h/mL) in rats as compared to GW7604 (AUC = 3.35 μg×h/mL). The strikingly favorable pharmacokinetic property of GLL398 makes it a promising oral non-steroidal SERD suitable for clinical evaluation. These studies disclose the superiority of boronic acid as a pharmacophore enhancing the enrichment of active pharmaceutical ingredients in the circulation.

Application of the boronic acid as an isostere of the phenolic hydroxyl group in optimization of Selective Estrogen Receptor Downregulators (SERDs)

253rd National Meeting (2017)

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