Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

Abstract

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

Tetrahydroisoquinoline Phenols: Selective Estrogen Receptor Downregulator Antagonists with Oral Bioavailability in Rat

“…12 With the addition of the acrylic acid functionality to the THIQ scaffold, N-phenyl (7) and N-benzyl (8) THIQs were shown to bind to the receptor and have a downregulator-antagonist phenotype. Exploration of the SAR around the phenyl ring identified that activity in the binding and downregulation assays could be increased by the addition of substituents such as p-OCF 3 (9), consistent with previously reported SAR, 5 but the compounds were too lipophilic (logD 7.4 3.7) and highly bound to plasma proteins (Rat PPB 0.06% free). As an alternative approach, we also examined N-alkyl substituents such as i Bu (10), which allowed a shift to lower lipophilicity space (logD 7.4 1.3) while maintaining downregulator-antagonist activity.…”

“…We recently reported our initial attempts to develop a coumarin based series of SERDs. 5 Further efforts in this area have resulted in the disclosure of 3 (ARN-810) 6 and 4 (AZD9496), 7 both of which are currently in Phase I clinical trials. Herein we report an investigation, carried out in parallel to the discovery of 4, on a phenolic tetrahydroisoquinoline (THIQ) scaffold with the aim of identifying a potent, orally bioavailable SERD.…”

“…As expected, both compounds lost significant activity in both the binding and downregulation assays consistent with loss of the phenol interaction seen in the Xray crystal structures and our previously reported findings. 5 Notably, the compounds without the phenol showed no activity in a GSH trapping assay, whereas phenol 12 showed a small but reproducible signal potentially indicating a reactive metabolite risk.…”

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive andESR1-Mutant Breast Tumors in Preclinical Models

“…This model contains high circulating levels of plasma estradiol over the dosing period of the study as a result of the estrogen pellets used to drive growth of the MCF-7 cells as a xenograft. With plasma levels between 750 and 1,000 pg/mL over day [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], this model is more representative of the premenopausal setting where estrogen levels can vary between 20 and 400 pg/mL (47). As the receptor binding data does not suggest a significant difference in affinity for the receptor between AZD9496 and fulvestrant, increased efficacy is likely due to the higher free drug levels of AZD9496 versus fulvestrant in this model.…”

“…Protein production, crystallization, and structure determination Protein expression, purification, and crystallization of the ERa ligand-binding domain was carried out as described previously (24). X-ray diffraction data were collected at the ESRF on beamline ID23-1 on an ADSC detector.…”