Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function

Edgardo Laborde, Robert W Macsata, Fanying Meng, Brian T Peterson, Louise Robinson, Steve R Schow, Reyna J Simon, Hua Xu, Kunihisa Baba, Hideaki Inagaki, Yoshiro Ishiwata, Takahito Jomori, Yukiharu Matsumoto, Atsushi Miyachi, Takashi Nakamura, Masayuki Okamoto, Tracy M Handel, Claude CA Bernard

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    Abstract

    Through the application of TRAP (target-related affinity profiling), we identified a novel class of heteroaroylphenylureas that inhibit human CCL2-induced chemotaxis of monocytes/macrophages both in vitro and in vivo. This inhibition was concentration-dependent and selective with regard to other chemokines. The compounds, however, did not antagonize the binding of (125)I-labeled CCL2 to the CCR2 receptor nor did they block CCR2-mediated signal transduction responses such as calcium mobilization. Optimization of early leads for potency and pharmacokinetic parameters resulted in the identification of 17, a potent inhibitor of chemotaxis (IC(50) = 80 nM) with excellent oral bioavailability in rats (F = 60 ). Compound 17 reduced swelling and joint destruction in two rat models of rheumatoid arthritis and delayed disease onset and produced near complete resolution of symptoms in a mouse model of multiple sclerosis.
    Original languageEnglish
    Pages (from-to)1667 - 1681
    Number of pages15
    JournalJournal of Medicinal Chemistry
    Volume54
    Issue number6
    DOIs
    Publication statusPublished - 2011

    Cite this

    Laborde, E., Macsata, R. W., Meng, F., Peterson, B. T., Robinson, L., Schow, S. R., Simon, R. J., Xu, H., Baba, K., Inagaki, H., Ishiwata, Y., Jomori, T., Matsumoto, Y., Miyachi, A., Nakamura, T., Okamoto, M., Handel, T. M., & Bernard, C. CA. (2011). Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function. Journal of Medicinal Chemistry, 54(6), 1667 - 1681. https://doi.org/10.1021/jm1012903