769971-54-2Relevant academic research and scientific papers
Discovery, optimization, and pharmacological characterization of novel heteroaroylphenylureas antagonists of C-C chemokine ligand 2 function
Laborde, Edgardo,MacSata, Robert W.,Meng, Finying,Peterson, Brian T.,Robinson, Louise,Schow, Steve R.,Simon, Reyna J.,Xu, Hua,Baba, Kunihisa,Inagaki, Hideaki,Ishiwata, Yoshiro,Jomori, Takahito,Matsumoto, Yukiharu,Miyachi, Atsushi,Nakamura, Takashi,Okamoto, Masayuki,Handel, Tracy M.,Bernard, Claude C. A.
experimental part, p. 1667 - 1681 (2011/05/07)
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 125I-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 (IC50 = 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.
Antagonist of MCP-1 function, and compositions and methods of use thereof
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, (2008/06/13)
Compounds of formula A and formula B: and their pharmaceutically acceptable salts, compositions comprising them, methods for their use, and their use in the preparation of medicaments. The compounds are antagonists of MCP-1 function, and are useful in the prevention and treatment of chronic or acute inflammatory or autoimmune diseases, such as multiple sclerosis, and in the prevention and treatment of allergic hypersensitivity disorders.
