Discovery of G Protein-Biased EP2 Receptor Agonists

Abstract

To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors.

Keywords: EP2; Prostaglandin; agonist; biased ligand; structure−functional selectivity relationship.

Figure 1

Reported EP2 agonists.

Figure 2

Design of novel EP2 agonists with unique bicyclic scaffold.

Scheme 1. Syntheses of Compounds 8, 11a–e, and 18a–n

Reagents and conditions: (a) Dess–Martin periodinane, CH₂Cl₂, 0 °C, 77%; (b) 19, 20, or 21, KHMDS, DME, 0 °C, 18–66%; (c) 2 mol/L NaOHaq, DME, MeOH, rt, 56–96%; (d) TsNHNH₂, NaOAc, EtOH, H₂O, 80 °C, 55–71%, (e) TBAF, THF, rt, 96%; (f) DEAD, Ph₃P, THF, rt, 82%; (g) i-PrI, K₂CO₃, DMF, rt, 54%; (h) PPTS, CH₂Cl₂, DHP, rt; (i) (methoxymethyl)triphenylphospine chrolide, KOtBu, THF, rt, 64%; (j) TsOH, acetone, H₂O, rt, 78%; (k) Ac₂O, Py, rt, 82%; (l) NaBH₄, THF, rt, 61%; (m) phenol analogues, TMAD, Bu₃P, THF, rt, 61–92%. Syntheses of common intermediate 9 and Julia–Kocienski reagents 19–21 are shown in the Supporting Information.