强效咪唑并吡啶抗寄生虫药的合成及构效关系研究
Synthesis and SAR studies of very potent imidazopyridine antiprotozoal agents.
作者信息
Biftu Tesfaye, Feng Dennis, Fisher Michael, Liang Gui-Bai, Qian Xiaoxia, Scribner Andrew, Dennis Richard, Lee Shuliang, Liberator Paul A, Brown Chris, Gurnett Anne, Leavitt Penny S, Thompson Donald, Mathew John, Misura Andrew, Samaras Samantha, Tamas Tamas, Sina Joseph F, McNulty Kathleen A, McKnight Crystal G, Schmatz Dennis M, Wyvratt Matthew
机构信息
Merck Research Laboratories, Department of Medicinal Chemistry, Merck and Co., Inc, PO Box 2000, Rahway, NJ 07065, USA.
出版信息
Bioorg Med Chem Lett. 2006 May 1;16(9):2479-83. doi: 10.1016/j.bmcl.2006.01.092. Epub 2006 Feb 7.
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.
化合物10a（IC50为110皮摩尔）和21（IC50为40皮摩尔）是迄今为止报道的对柔嫩艾美耳球虫环磷酸鸟苷依赖性蛋白激酶活性最有效的抑制剂，当以12.5和6.25 ppm的水平添加到鸡饲料中进行体内抗寄生虫试验时，它们是有效的。然而，这两种化合物在艾姆斯微生物诱变试验中呈阳性，这使得它们在缺乏啮齿动物终身致癌性阴性研究的情况下，无法作为抗原生动物药物进一步开发。
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