Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).

The interaction between CC chemokine receptor 2 (CCR2) with monocyte chemoattractant proteins, such as MCP-1, regulates the activation and recruitment of inflammatory leukocytes. In this study, we characterized (S)-3-[3,4-difluoro-phenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl acid methyl ester (JNJ-27141491) as a noncompetitive and orally active functional antagonist of human (h)CCR2. JNJ-27141491 strongly suppressed hCCR2-mediated in vitro functions, such as MCP-1-induced guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding; MCP-1, -3, and -4-induced Ca 2ϩ mobilization; and leukocyte chemotaxis toward MCP-1 (IC 50 ϭ 7-97 nM), whereas it had little or no effect on the function of other chemokine receptors tested. The inhibition of CCR2 function was both insurmountable and reversible, consistent with a noncompetitive mode of action. JNJ-27141491 blocked the binding of CCR2 is a G protein-coupled chemokine receptor, expressed on monocytes, macrophages, basophils, dendritic cells, natural killer cells, and activated T lymphocytes, that mediates the activation and movement of responsive leukocytes along a chemotactic gradient. CCR2 has two isoforms (CCR2A and CCR2B) that are generated by alternative splicing and differ only in their carboxyl-terminal tail. Leukocytes predominantly express the longer CCR2B variant (Tanaka et al., 2002). CCR2B (henceforth called CCR2) is activated by several members of the CC-chemokine subfamily, consisting of monocyte chemoattractant protein-1 (MCP-1/CCL2), MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, and MCP-5/CCL16. MCP-1 exclusively interacts with CCR2 and is therefore recognized as the prime CCR2 agonist. Engagement of CCR2 inhibits adenylyl cyclase, promotes intracellular calcium mobilization, stimulates mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways, and promotes che-

We recently reported the discovery of a series of 2-thioimidazoles as CCR2 antagonists. The most potent molecules of this series, the 4,5-diesters, were rapidly hydrolyzed to the inactive acids and were found to be metabolically unstable. Herein we describe the synthesis of a number of analogues with heterocyclic bioisosteric replacements of the ester group(s). Small 5-membered heterocyclic substituents at the 4-position gave highly potent CCR2 antagonists. Hydrolysis of the 5-ester is diminished, thus imparting these compounds with sufficient stability and systemic exposure after oral administration to warrant further study of the in vivo pharmacology of these functional CCR2 inhibitors.

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Novel tricyclic tetrahydroazepinones were synthesized via an in situ Diels-Alder reaction of furan with cyclic allenamides. These reactive intermediates are the first examples of cyclic seven-membered allenamides and were prepared starting from N-(2-chloroallyl)-2-allylglycine derivatives via ring-closing metathesis followed by dehydrochlorination. The trapping of the intermediate cycloallene with furan occurred endo- and regioselectively and provided a convenient entry into new building blocks for medicinal chemistry. The diastereoselectivity of the cycloaddition was confirmed using quantum chemical computations.