2-Mercaptoimidazoles, a new class of potent CCR2 antagonists

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Abstract

We describe the synthesis and SAR of a new class of CCR2 antagonists based on a 2-mercaptoimidazole scaffold. The initial lead 1a was optimized to the 3,4-disubstituted analogues 1p-(S) and 1q-(S), which have IC50 values in the MCP-1 induced Ca-flux below 0.01 μM.

Graphical abstract

The synthesis and SAR of a new class of CCR2 antagonists based on the lead compound 1a are described. The optimization of the initial lead delivered nanomolar inhibitors of the MCP-1 induced Ca-flux in human THP-1 cells.

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Introduction

Monocyte chemoattractant protein-1 (MCP-1) and its receptor (CCR2) have been implicated in a number of inflammatory and autoimmune diseases,1 in particular, by affecting monocyte infiltration. So antagonists of the CCR2 receptor are potential therapeutic agents for various pathological conditions such as rheumatoid arthritis,2 multiple sclerosis,3 COPD4 and atherosclerosis.5

Recently a number of small molecule antagonists of this receptor have been described6, 7, 8, 9, 10, 11 and a common characteristic of their binding site was proposed.12

In a high throughput screening based on MCP-1 induced GTPγS binding in human CCR2B-CHO cell membranes, we identified the mercaptoimidazole 1a as a new promising lead compound, its activity was confirmed in an assay based on MCP-1 induced calcium flux in THP-1 cells14 IC50: 0.2 μM.

Herein we describe the SAR in this new class of CCR-2 antagonists.

Section snippets

Chemistry

The mercaptoimidazoles were synthesized as described in Scheme 1. Starting ketones and amines were prepared by literature procedures, previously undescribed ketones could be obtained by Friedel–Crafts reactions of an acylchloride with the appropriate substituted benzene derivative. Enantiomers were obtained similarly using optically pure amines synthesized as described in Scheme 2.13

4,5-Disubstituted imidazoles can be prepared following Scheme 1 but using dimethyloxalate rather than

Structure–activity relationship

Analysis of the high throughput screening data pointed to the importance of the 3,4-dichloro substitution on the phenyl ring. Analogues with other substituents on the phenyl (mono- or di-methyl or methoxy, and mono-halo or phenoxy) were less active. The mercapto group seemed essential for activity, desulfurized analogues were devoid of activity. Also variation in the length of the benzylic spacer led to compounds with markedly reduced potency.

To get a better idea about the SAR in this series a

References and notes (15)

  • L. Izikson et al.

    Clin. Immunol.

    (2002)
  • T. Mirzadegan et al.

    J. Biol. Chem.

    (2000)
  • M. Shiraishi et al.

    J. Med. Chem.

    (2000)
  • W. Moree et al.

    Bioorg. Med. Chem. Lett.

    (2004)
  • T.A. Berkhout et al.

    J. Med. Chem.

    (2003)
  • J. Dawson et al.

    Expert Opin. Ther. Targets

    (2003)
There are more references available in the full text version of this article.

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