Alpha-aminothiazole-gamma-aminobutanoic amides as potent, small molecule CCR2 receptor antagonists |
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Authors: | Zhou Changyou Guo Liangqin Parsons William H Mills Sander G MacCoss Malcolm Vicario Pasquale P Zweerink Hans Cascieri Margaret A Springer Martin S Yang Lihu |
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Institution: | Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. changyou_zhou@merck.com |
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Abstract: | A series of racemic and homochiral alpha-aminothiazole-gamma-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-2-(acetylamino)-1,3-thiazol-4-yl]-N-3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM. |
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