Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the MCP-1 receptor, CCR2, a member of the G-proteincoupled seven-transmembrane receptor superfamily. These studies identified a family of antagonists, spiropiperidines. One of the more potent compounds blocks MCP-1 binding to CCR2 with a K d of 60 nM, but it is unable to block binding to CXCR1, CCR1, or CCR3. These compounds were effective inhibitors of chemotaxis toward MCP-1 but were very poor inhibitors of CCR1-mediated chemotaxis. The compounds are effective blockers of MCP-1-driven inhibition of adenylate cyclase and MCP-1-and MCP-3-driven cytosolic calcium influx; the compounds are not agonists for these pathways. We showed that glutamate 291 (Glu 291 ) of CCR2 is a critical residue for high affinity binding and that this residue contributes little to MCP-1 binding to CCR2. The basic nitrogen present in the spiropiperidine compounds may be the interaction partner for Glu 291 , because the basicity of this nitrogen was essential for affinity; furthermore, a different class of antagonists, a class that does not have a basic nitrogen (2-carboxypyrroles), were not affected by mutations of Glu 291 . In addition to the CCR2 receptor, spiropiperidine compounds have affinity for several biogenic amine receptors. Receptor models indicate that the acidic residue, Glu 291, from transmembrane-7 of CCR2 is in a position similar to the acidic residue contributed from transmembrane-3 of biogenic amine receptors, which may account for the shared affinity of spiropiperidines for these two receptor classes. The models suggest that the acid-base pair, Glu 291 to piperidine nitrogen, anchors the spiropiperidine compound within the transmembrane ovoid bundle. This binding site may overlap with the space required by MCP-1 during binding and signaling; thus the small molecule ligands act as antagonists. An acidic residue in transmembrane region 7 is found in most chemokine receptors and is rare in other serpentine receptors. The model of the binding site may suggest ways to make new small molecule chemokine receptor antagonists, and it may rationalize the design of more potent and selective antagonists.Chemokines are a large family of small proteins that mediate attraction of leukocytes to inflammatory sites (1-3). The chemokine family shares a common pattern of disulfide bonds and a common overall tertiary structure as shown in solution or crystallographically determined structures (4 -6). The chemokine family is divided into four subfamilies based on the number of residues between the first and second cysteine. Among the chemokines, the CC chemokine monocyte chemoattracant-1 (MCP-1) 1 has received a great deal of attention because of its involvement in diseases. MCP-1 expression is elevated in the inflamed synovium of rheumatoid arthritis, and its expression is reduced by anti-arthritic drugs (7,8). Other work has shown that MCP-1 is elevated in asthmatic patients; the am...

Transition-metal-catalyzed cross-coupling reactions play a major role in the formation of C À C bonds. As a result, the cross-coupling of aryl halides (and pseudohalides) with organometallic reagents have become a steadfast method in organic synthesis.[1] This methodology has been used to prepare biaryl compounds, which are prevalent in both natural products and drug compounds.[2] In the more challenging cross-coupling reactions unreactive substrates, such as aryl nitriles, [3] aryl fluorides, [4] and aryl carbamates [5] are coupled with an organometallic reagent and generally require nickel catalysis. Wenkert et al. reported the [NiCl 2 (PPh 3 ) 2 ]-mediated cross-coupling of anisoles with aromatic Grignard reagents.[6] The scope of this process is rather limited, and the only substrates that provide the desired biaryl products in synthetically useful yields are the more reactive 1-and 2-methoxynaphthalene derivatives. In this communication, we report a general, high-yielding nickel-catalyzed cross-coupling of nonactivated aromatic ethers with aryl Grignard reagents.Our initial attempts in cross-coupling an anisole derivative with p-TolMgBr utilized a nickel catalyst prepared in situ from [Ni(acac) 2 ] (acac = acetylacetonyl) and various phosphane ligands in THF. Unfortunately, the reaction did not proceed to completion under any of the conditions tested (Table 1). From these studies, it was found that PCy 3 (Cy = cyclohexyl), an electron-rich ligand, was the best phosphane ligand with [Ni(acac)

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Aryl nitriles have been found to participate in cross-coupling and amination reactions via nickel-catalyzed activation of the C-CN bond. With the development of these synthetically useful transformations, aryl nitriles can now be considered along with aryl halides and sulfonates as viable substrates for these types of reactions.

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