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

Abstract

A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.

The Quest for Orally Available Selective Estrogen Receptor Degraders (SERDs)

“…Smith and co-workers replaced basic substituent with an acrylic acid, affording the N-phenyl 37 and N-benzyl 38 THIQs, which were shown to bind to ERα and to have a downregulation IC 50 in the mid nanomolar range. [26] The introduction of an N-isobutyl substituent (39) shifted the log D value to a lower lipophilicity space (log D = Consistent with previous reports, [30] the 3-(R)-methyl group is able to fill the Phe404 : Phe425 lipophilic pocket ( Figure 5). Addition of a 3-fluoro to the alkyl chain (42) provided a subnanomolar downregulator (ERα degradation IC 50 = 0.25 nM) [a] Bioavailability after oral administration (1 mg/kg iv, 3 mg/kg po) [b] Not determined.…”

“…The 1-methyl group was hypothesized to enhance potency by increasing lipophilicity while not affecting binding properties, as shown with previous antiestrogens. [26] The p-isopropyl substituent causes conformational adjustments which mimic that seen in the ERα-GW5638 complex, resulting in an altered van der Waals interaction network that allows for less flexibility within the typical dynamic hydrophobic core.…”

Targeted Protein Degradation by Small Molecules

“…With improved oral bioavailability, this compound shows promising preclinical results in mice (12–14) and is now in Phase I clinical trials. Other compounds with oral bioavailability and high potency have also been described by AstraZeneca (15–19), Pfizer (20), and other research groups (21). …”

Alangium longiflorum Merr. Leaf Extract Induces Apoptosis in A549 Lung Cancer Cells with Minimal NFκB Transcriptional Activation

“…MCF-7 contains estrogen receptors which increases cell proliferation and pro-survival signaling upon ligand activation (Jameera Begam et al, 2017). It is interesting to speculate that the presence of phenolic compounds in AL may cause strong growth inhibition in MCF-7, as phenolic compounds can antagonize estrogen receptors (Scott et al, 2016;Pang et al, 2018). Further studies need to be done to investigate the contribution of different components of the extract and to elucidate the mechanism of action between MCF-7 and A549.…”