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. 2019 Sep 23;10(10):1492-1497.
doi: 10.1021/acsmedchemlett.9b00370. eCollection 2019 Oct 10.

Building Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry

James S Scott  1 , Jason Breed  2 , Rodrigo J Carbajo  1 , Paul R Davey  1 , Ryan Greenwood  1 , Hoan K Huynh  3 , Teresa Klinowska  1 , Christopher J Morrow  1 , Thomas A Moss  1 , Radoslaw Polanski  2 , J Willem M Nissink  1 , Jeffrey Varnes  3 , Bin Yang  3
Affiliations

Building Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry

James S Scott et al. ACS Med Chem Lett. .

Abstract

Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected oral SERDs AZD9496 (1), RAD1901 (2), and GDC0927 (3).
Scheme 1
Scheme 1. Synthesis of Methyl Substituted Core 4
Reagents and conditions: (i) Cerium(IV) ammonium nitrate, 4:1 MeCN/H2O, r.t. (ii) MeMgBr, THF, −10 °C, 27% over 2 steps. (iii) aq. NaOH, 1:1 MeOH/THF, r.t. 75%.
Figure 2
Figure 2
Rationale for construction of bridged scaffolds.
Scheme 2
Scheme 2. Synthesis of Cyclized Core 7, 8, and 17
Reagents and conditions: (i) SO3·Py, Et3N, 1:1 DCM/DMSO, 0 °C, 87%. (ii) Methyltriphenylphosphonium bromide, 1 M KHMDS solution, THF, −78 °C, 40%. (iii) Cerium(IV) ammonium nitrate, 4:1 MeCN, H2O, r.t. (iv) AllylMgBr, THF, −10 °C, 18% over 2 steps. (v) Grubbs (II) catalyst, toluene, 60 °C, 93%. (vi) Methyl acrylate, Pd118, DIPEA, 1,4-dioxane, 140 °C, MW, 58–64%. (vii) aq. NaOH, 1:1 MeOH/THF, r.t. 90–91%. (viii) PtO2, H2, EtOAc, r.t. 100%. (ix) Azetine alcohol, rockphos PdG3, Cs2CO3, toluene, 100 °C, 25%.
Figure 3
Figure 3
X-ray crystallography of ligands bound to the ERα ligand binding domain construct: (a) 8 (purple pdb code 6sq0); (b) 8 overlaid with 1 (orange, pdb code 5acc); (c) 6 (green pdb code 6suo) overlaid with 8. (d) 19F{1H} NMR suggests slow rotation of the difluorophenyl ring for 1; (e) rotational locking is observed for bridged core 8; (f) methylated core 6 shows slow rotation, as for 1. For 6, sharp F signals were observed for the alkene degradant product, and these have been indicated.
Figure 4
Figure 4
Curves from the degradation assay showing differential behavior for the bridged (8, 17) relative to the methyl-substituted cores (6, 16).
See this image and copyright information in PMC

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