Structure–activity relationship of cinnamic acylsulfonamide analogues on the human EP3 prostanoid receptor

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Abstract

Potent and selective antagonists of the human EP3 receptor have been identified. The structure–activity relationship of the chemical series was conducted and we found several analogues displaying sub-nanomolar Ki values at the EP3 receptor and micromolar activities at the EP1, EP2 and EP4 receptors. The effect of added human serum albumin (HSA) on the binding affinity at the EP3 receptor was also investigated.

The structure–activity of the cinnamic acylsulfonamide series was conducted. Potent and selective antagonists of the human EP3 receptor displaying sub-nanomolar Ki values were identified.

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Introduction

In response to various extracellular stimuli, prostaglandins are rapidly generated through the consecutive action of the cyclo-oxygenases and distinct synthases on membrane arachidonic acid and exert their action in close proximity to the site of their synthesis. The eight known human prostanoid receptors have been cloned and their sequences determined.1 PGE2 will bind preferentially to the EP1, EP2, EP3 and EP4 receptors, PGD2 to the DP receptor, PGF to the FP receptor, PGI2 to the IP receptor and TXA2 to the TP receptor.2, 3 The pharmacological action of the prostanoids at their respective receptors results ultimately in a variety of biological responses in different tissues. PGE2 binding to the EP3 receptor has been found to play a key role in the regulation of ion transport, smooth muscle contraction of the GI tract, acid secretion, uterine contraction during fertilization and implantation, fever generation and PGE2-mediated hyperalgesia. The EP3 receptor has been detected in many organs such as the kidney, the gastrointestinal tract, the uterus and the brain.4 So far, studies for understanding the roles of EP3 have been conducted mainly with PGE2 and other prostanoid-like compounds.5 However, these compounds behave as agonists and cross react with other prostanoid receptors. The lack of selective and specific EP3 antagonists has become a crucial issue for the characterization of the EP3 receptor pharmacology.

Section snippets

Results and discussion

Recently, we have reported a new class of EP3 antagonist based on the arylmethyl cinnamic acid skeleton Scheme 1, Scheme 2.6 This series was found to be active at the EP3 receptor with Ki values between 20 and 100 nM for the most potent analogues.7 The three step synthesis of this class of compounds is illustrated in Scheme 1. A Suzuki coupling reaction was first performed between the benzyl bromide 2 and an aryl boronic acid. Hydrolysis under basic conditions gave the desired arylmethyl

Conclusion

We have described the SAR studies in the arylmethyl cinnamic acylsulfonamide series that allowed identification of compounds with nanomolar potency on the human EP3 receptor and high selectivity over the other EP receptors.10 One of them, compound 11b, was 0.6 nM at the EP3 receptor and 4.1 nM in the presence of HSA (7-fold shift). This compound was also highly selective over the other EP receptors. Pharmacological studies of this compound will be disclosed elsewhere.

Biological assays

See ref 2 for stable expression of prostanoid receptors in the human embryonic kidney (HEK) 293 (EBNA) cell line and also for prostanoid receptor binding assays.

General procedure for the preparation of cinnamate ester. Methyl-3-(2-methylphenyl)-2-propenoate (1a)

To a solution of 2-methylcinnamic acid (100.0 g, 617 mmol) in 1.2 L of DMF was added DBU (112.6 g, 740 mmol). After 15 min, methyl iodide (131.3 g, 925 mmol) was added dropwise and the mixture was stirred overnight. The solution was then diluted in ether and washed with HCl (10%), water and brine. The solvent was removed to give 106.8 g

Acknowledgements

The authors would like to thank Dr. John Colucci for proofreading this manuscript.

References (13)

  • C.D Funk et al.

    J. Biol. Chem.

    (1993)
    J.W Regan et al.

    Mol. Pharmacol.

    (1994)
    M Adam et al.

    FEBS Lett.

    (1994)
    L Bastien et al.

    J. Biol. Chem.

    (1994)
    Y Boie et al.

    J. Biol. Chem.

    (1995)
    M Abramovitz et al.

    J. Biol. Chem.

    (1994)
    Y Boie et al.

    J. Biol. Chem.

    (1994)
    M Hirata et al.

    Nature

    (1991)
  • A Kiryiama et al.

    Br. J. Pharmacol.

    (1997)
  • Y Sugimoto et al.

    Prog. Lipid. Res.

    (2000)
    S Narumiya et al.

    Physiol. Rev.

    (1999)
    R.A Coleman et al.

    Pharmacol. Rev.

    (1994)
  • Y Shimazaki et al.

    Bioorg. Med. Chem.

    (2000)
  • Juteau, H.; Gareau, Y.; Labelle, M.; Lamontagne, S.; Tremblay, N.; Carriere, M. C.; Sawyer, N.; Denis, D.; Metters, K....
  • The subtype used for this assay was...
There are more references available in the full text version of this article.

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