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. 2016 Jan 4;7(3):306-11.
doi: 10.1021/acsmedchemlett.5b00455. eCollection 2016 Mar 10.

Discovery of G Protein-Biased EP2 Receptor Agonists

Seiji Ogawa  1 , Toshihide Watanabe  2 , Isamu Sugimoto  2 , Kazumi Moriyuki  2 , Yoshikazu Goto  2 , Shinsaku Yamane  2 , Akio Watanabe  2 , Kazuma Tsuboi  2 , Atsushi Kinoshita  2 , Hideo Kigoshi  3 , Kousuke Tani  2 , Toru Maruyama  2
Affiliations

Discovery of G Protein-Biased EP2 Receptor Agonists

Seiji Ogawa et al. ACS Med Chem Lett. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Reported EP2 agonists.
Figure 2
Figure 2
Design of novel EP2 agonists with unique bicyclic scaffold.
Scheme 1
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.
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