基于卤代乙脒的蛋白质精氨酸脱亚氨酶4（PAD4）失活剂的改进合成方法。
An improved synthesis of haloaceteamidine-based inactivators of protein arginine deiminase 4 (PAD4).
作者信息
Causey Corey P, Thompson Paul R
机构信息
Departent of Chemstry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, SC 29208.
出版信息
Tetrahedron Lett. 2008 Jul 7;49(28):4383-4385. doi: 10.1016/j.tetlet.2008.05.021.
Abstract
Protein arginine deiminase 4 (PAD4) is an enzyme that hydrolyzes peptidyl arginine residues to form citrulline and ammonia. This enzyme has been implicated in several disease states, e.g. rheumatoid arthritis, and therefore represents a unique target for the development of a novel therapeutic. A solution-phase synthesis of Cl-amidine, the most potent PAD4 inactivator described to date, has been developed. This synthesis proceeds in 80% yield over 4 steps at a significantly (12-fold) lower cost.
摘要
蛋白质精氨酸脱亚氨酶4（PAD4）是一种将肽基精氨酸残基水解以形成瓜氨酸和氨的酶。这种酶与多种疾病状态有关，例如类风湿性关节炎，因此是新型治疗药物开发的独特靶点。已开发出迄今为止描述的最有效的PAD4灭活剂Cl-脒的溶液相合成方法。该合成方法以80%的产率分4步进行，成本显著降低（12倍）。
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Arthritis Rheum. 2007 Nov;56(11):3541-53. doi: 10.1002/art.22983.
2
PADI4 polymorphisms and rheumatoid arthritis susceptibility: a meta-analysis.
Rheumatol Int. 2007 Jul;27(9):827-33. doi: 10.1007/s00296-007-0320-y. Epub 2007 Jan 31.
3
Modulation of peptidyl arginine deiminase 2 and implication for neurodegeneration.
Curr Eye Res. 2006 Dec;31(12):1063-71. doi: 10.1080/02713680600991437.
4
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5
Very recent onset rheumatoid arthritis: clinical and serological patient characteristics associated with radiographic progression over the first years of disease.
Rheumatology (Oxford). 2007 Feb;46(2):342-9. doi: 10.1093/rheumatology/kel237. Epub 2006 Aug 9.
6
Proteomics implicates peptidyl arginine deiminase 2 and optic nerve citrullination in glaucoma pathogenesis.
Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2508-14. doi: 10.1167/iovs.05-1499.
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Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4.
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