2-Mercaptoimidazoles, a new class of potent CCR2 antagonists
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.
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)
- et al.
Clin. Immunol.
(2002) - et al.
J. Biol. Chem.
(2000) - et al.
J. Med. Chem.
(2000) - et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
J. Med. Chem.
(2003) - et al.
Expert Opin. Ther. Targets
(2003)
Cited by (36)
2-Seleno-1-alkylbenzimidazoles and their diselenides: Synthesis and structural characterization of a 2-seleno-1-methylbenzimidazole complex of mercury
2013, PolyhedronCitation Excerpt :An illustration of the flexibility of dative Hg←Se interactions is provided by the observation that the Hg–Se bonds within [Hg2(SePh2)4][ClO4]2 vary from 2.65 to 2.92 Å [37]. For further comparison, the mean Hg–Se bond length for compounds listed in the Cambridge Structural Database [38] is 2.660 Å, and a selection of such compounds is listed in Table 1 [39–45,32,46–48]. Coordination of H(sebenzimMe) is accompanied by a relatively small lengthening of the C–Se bond.
Design, synthesis and SAR of indazole and benzoisoxazole containing 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists
2011, Bioorganic and Medicinal Chemistry LettersOvercoming hERG activity in the discovery of a series of 4-azetidinyl-1-aryl-cyclohexanes as CCR2 antagonists
2011, Bioorganic and Medicinal Chemistry LettersDiscovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2
2010, Bioorganic and Medicinal Chemistry Letters