The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors.
The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors.
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DOI：
10.1021/jm2008985
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发表时间：
2011-10-13
影响因子：
7.3
通讯作者：
Thompson, Paul R.
中科院分区：
文献类型：
--
作者：
Causey, Corey P.;Jones, Justin E.;Slack, Jessica L.;Kamei, Daisuke;Jones, Larry E., Jr.;Subramanian, Venkataraman;Knuckley, Bryan;Ebrahimi, Pedram;Chumanevich, Alexander A.;Luo, Yuan;Hashimoto, Hiroshi;Sato, Mamoru;Hofseth, Lorne J.;Thompson, Paul R.
蛋白质精氨酸脱亚胺酶（PAD）活性在许多人类疾病中上调，包括类风湿性关节炎、溃疡性结肠炎和癌症。这些酶，在人类中有五种（PADs 1-4和6）调节基因转录，细胞分化和先天免疫反应。在我们成功产生的F-和Cl-脒（其不可逆地抑制所有PAD）的基础上，进行了结构活性关系，以开发具有改善的效力和选择性的第二代化合物。在骨架酰胺的邻位引入羧酸酯导致鉴定出N-α-（2-羧基）苯甲酰基-N5-（2-氟-1-亚氨基乙基）-L-鸟氨酸酰胺（o-F-脒）和Nα-（2-羧基）苯甲酰基-N5-（2-氯-1-亚氨基乙基）-L-鸟氨酸酰胺（o-Cl-脒）作为PAD灭活剂，具有改善的效力（高达65倍）和选择性（高达25倍）。相对于F-和Cl-脒，该化合物在纤维素中也显示出增强的效力。因此，这些化合物将是PAD功能的通用化学探针。
Protein Arginine Deiminase (PAD) activity is upregulated in a number of human diseases, including rheumatoid arthritis, ulcerative colitis, and cancer. These enzymes, there are five in humans (PADs 1-4 and 6) regulate gene transcription, cellular differentiation, and the innate immune response. Building on our successful generation F- and Cl-amidine, which irreversibly inhibit all of the PADs, a structure activity relationship was performed to develop second generation compounds with improved potency and selectivity. Incorporation of a carboxylate ortho to the backbone amide resulted in the identification of N-α-(2-carboxyl)benzoyl-N5-(2-fluoro-1-iminoethyl)-L-ornithine amide (o-F-amidine) and Nα-(2-carboxyl)benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (o-Cl-amidine), as PAD inactivators with improved potency (up to 65-fold) and selectivity (up to 25-fold). Relative to F- and Cl-amidine, the compounds also show enhanced potency in cellulo. As such, these compounds will be versatile chemical probes of PAD function.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.3
作者：
Li, Pingxin;Yao, Hongjie;Wang, Yanming
通讯作者：
Wang, Yanming
影响因子：
7.2
作者：
Liu, GY;Liao, YF;Hung, HC
通讯作者：
Hung, HC
影响因子：
2.9
作者：
Knuckley, Bryan;Causey, Corey P.;Jones, Justin E.;Bhatia, Monica;Dreyton, Christina J.;Osborne, Tanesha C.;Takahara, Hidenari;Thompson, Paul R.
通讯作者：
Thompson, Paul R.