Jones M M, Singh P K, Zimmerman L J, Gomez M, Albina M L, Domingo J L
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, USA.
Chem Res Toxicol. 1995 Oct-Nov;8(7):942-8. doi: 10.1021/tx00049a007.
In order to estimate the potential advantages of new chelating agents which can enhance copper excretion in the chronic copper intoxication arising in Wilson's disease, the relative ability of none chelating agents to induce the urinary excretion of copper was compared with that of D-penicillamine (DPA) and triethylenetetramine.2HCl (TRIEN), all given ip at 1 mmol/kg to male Sprague-Dawley rats. The compounds examined were as follows: tris(2-aminoethyl)-amine.3HCl (TREN), tetraethylenepentamine.5HCl (TETREN), pentaethylenehexamine.6HCl (PENTEN), 1,4,7,11-tetraazaundecane.4HCl (TAUD), 1,5,8,12-tetraazadodecane.4HCl (TADD), 1-N-benzyltriethylenetetramine.4HCl (BzTT), 4,7,10,13-tetraazatridecanoic acid.2H2SO4 (TTPA), 1,10-bis(2-pyridylmethyl)-1,4,7,10-tetraazadecane.4HCl (BPTETA), and N,N-bis(2-pyridylmethyl)-4-(aminomethyl)benzoic acid (4ABA). Of these, BzTT, TTPA, and 4ABA are new chelating agents not previously reported. The factors by which these chelating agents enhanced copper excretion over control (untreated) levels were as follows: DPA, 7.2; TREN, 1.6; TRIEN, 4.0; TETREN, 10.1; PENTEN, 7.8; TAUD, 7.8; TADD, 2.6; TTPA, 5.6; BzTT, 1.8; and 4ABA, 5.5. The results indicate that it may well be possible to develop additional chelating agents which are equal or superior to those now used in the treatment of Wilson's disease, as well as structural types whose immunological properties may be significantly different from DPA or TRIEN, the compounds currently used in the clinic for this disorder.
为了评估新型螯合剂在威尔逊病所致慢性铜中毒中增强铜排泄的潜在优势，将多种螯合剂诱导大鼠尿铜排泄的相对能力与D-青霉胺（DPA）和三乙烯四胺二盐酸盐（TRIEN）进行比较，所有药物均以1 mmol/kg的剂量腹腔注射给雄性斯普拉格-道利大鼠。所检测的化合物如下：三（2-氨基乙基）胺三盐酸盐（TREN）、五乙烯六胺五盐酸盐（TETREN）、六乙烯七胺六盐酸盐（PENTEN）、1,4,7,11-四氮杂十一烷四盐酸盐（TAUD）、1,5,8,12-四氮杂十二烷四盐酸盐（TADD）、1-N-苄基三乙烯四胺四盐酸盐（BzTT）、4,7,10,13-四氮杂十三烷酸二硫酸（TTPA）、1,10-双（2-吡啶甲基）-1,4,7,10-四氮杂十六烷四盐酸盐（BPTETA）和N,N-双（2-吡啶甲基）-4-（氨基甲基）苯甲酸（4ABA）。其中，BzTT、TTPA和4ABA是以前未报道过的新型螯合剂。这些螯合剂相对于对照（未处理）水平增强铜排泄的倍数如下：DPA为7.2；TREN为1.6；TRIEN为4.0；TETREN为10.1；PENTEN为7.8；TAUD为7.8；TADD为2.6；TTPA为5.6；BzTT为1.8；4ABA为5.5。结果表明，很有可能开发出与目前用于治疗威尔逊病的药物相当或更优的其他螯合剂，以及免疫特性可能与目前临床上用于治疗该疾病的DPA或TRIEN有显著差异的结构类型。
