Discovery of orally active prostaglandin D2 receptor antagonists

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Abstract

A series of N-(p-alkoxy)benzoyl-2-methylindole-4-acetic acids were synthesized and evaluated for prostaglandin D2 (DP) receptor affinity and antagonist activity. Some of them exhibited strong receptor binding and were potent in the cAMP formation assays. These antagonists also suppressed allergic inflammatory responses such as the PGD2-induced increase of microvascular permeability. Structure–activity relationship (SAR) data are presented.

Graphical abstract

Discovery process of a new PGD2 receptor antagonists 3i is reported.

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Introduction

Prostaglandin D2 (PGD2) is considered to play an important role in various allergic diseases such as allergic rhinitis,1 atopic asthma,2 allergic conjunctivitis,3 and atopic dermatitis.4 However, there have been very few reports about the efficacy of PGD2 receptor (DP) antagonists in animal models of allergy or patients with allergic diseases.5 A DP receptor selective antagonist was considered to possess potential therapeutic value for various allergic disorders.

In the preceding paper,6 we reported on the discovery of a new chemical lead 1 for DP receptor selective antagonists starting from the chemical modification of indomethacin analogs. Further optimization of the new chemical lead 1 was carried out. Modification of the chemical lead 1 was concentrated on the terminal alkyl moiety, which was still not optimized. The p-phenyloxyethyloxy derivative 2d showed the most potent mDP receptor antagonist activity among the compounds listed in Table 1. However, the human (h)DP receptor antagonist activity of 2d was found to be relatively lower than the mDP receptor antagonist activity as described in Table 1. Further optimization of 2d was continued to increase its hDP receptor antagonist activity.

Here we report on the identification of an orally active hDP receptor antagonist 3i, which exhibited efficacy in animal models, starting from chemical modification of 2d (Fig. 1).

Section snippets

Chemistry

A series of N-benzoyl-2-methylindole-4-acetic acids 1, 2ad, and 3ai listed in Table 1, Table 2 were synthesized as outlined in Scheme 1. Efficient synthetic method of 2-methylindole-4-acetic acid has been unknown. In the preceding paper,6 we reported on the synthesis of 2-methylindole-4-acetic acid using palladium-catalyzed carbon monoxide insertion reaction starting from 2-methyl-4-hydroxyindole 4a. Here we report on the more efficient synthesis consisting of palladium-catalyzed C2

Results and discussion

The compounds listed in Table 1, Table 2 were evaluated for inhibition of the specific binding of a radioligand, [3H]PGD2, to membrane fractions prepared from cells stably expressing each prostanoid receptor and for inhibition of cAMP formation evoked by PGD2 in CHO cells8 in the presence of BSA (0.1%). Test compounds were also evaluated for binding to all subtypes of the mouse PGE2 receptor (mEP1, mEP2, mEP3, and mEP4).9

In the preceding paper,6 we reported on the discovery of 1 as a new

References and notes (11)

  • W.J. Doyle et al.

    J. Allergy Clin. Immunol.

    (1990)
    S.L. Johnston et al.

    J. Allergy Clin. Immunol.

    (1993)
    K. Alving et al.

    Acta Physiol. Scand.

    (1991)
  • T. Matsuoka et al.

    Science

    (2000)
  • N.A. Powell et al.

    Tetrahedron Lett.

    (1996)
  • D.F. Woodward et al.

    Invest. Ophthalmol. Vis. Sci.

    (1990)
    D.F. Woodward et al.

    J. Pharmacol. Exp. Ther.

    (1996)
  • N.A. Soter et al.

    J. Invest. Dermatol.

    (1983)
    R.J. Flower et al.

    Br. J. Pharmacol.

    (1976)
There are more references available in the full text version of this article.

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