Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac.
Synthesis, characterization and pharmacological evaluation of amide prodrugs of ketorolac.
复制标题
酮咯酸酰胺前药的合成、表征及药理学评价。
DOI：
10.1016/j.ejmech.2007.09.011
复制
发表时间：
2008
影响因子：
6.7
通讯作者：
R. Agrawal
中科院分区：
文献类型：
--
作者：
A. Mishra;R. Veerasamy;P. Jain;V. Dixit;R. Agrawal
酮咯酸（KC）由于游离羧酸基团的存在而遭受NSAID的一般副作用。本研究旨在延缓胃肠道源性不良反应。以甘氨酸、L-苯丙氨酸、L-色氨酸、L-缬氨酸、L-异亮氨酸、L-丙氨酸、L-亮氨酸、L-谷氨酸、L-天冬氨酸和β-丙氨酸等氨基酸乙酯为原料，经酰胺化反应合成了10种KC前药。纯化的合成前药通过m. p.表征，TLC，溶解度，分配系数，元素分析，UV，FTIR，NMR和MS。合成的前药进行生物制药研究，镇痛，抗炎活性和溃疡指数。与KC相比，在所有病例中均获得了溃疡指数的显著降低和相当的镇痛、抗炎活性。在合成的前药中，即AR-11、AR-19和AR-20在SIF和80%人血浆中均显示出优异的药理学响应和令人鼓舞的水解率。具有增加的脂肪族侧链长度或引入芳香族取代基的前药显示增强的分配系数，但降低的溶解和水解速率。这样的前药可以考虑用于持续释放目的。
Ketorolac (KC) suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group. The study aimed to retard the adverse effects of gastrointestinal origin. Ten prodrugs of KC were synthesized by amidation with ethyl esters of amino acids, namely, glycine, l-phenylalanine, l-tryptophan, l-valine, l-isoleucine, l-alanine, l-leucine, l-glutamic acid, l-aspartic acid and β-alanine. Purified synthesized prodrugs were characterized by m.p., TLC, solubility, partition coefficients, elemental analyses, UV, FTIR, NMR and MS. Synthesized prodrugs were subjected for biopharmaceutical studies, analgesic, anti-inflammatory activities and ulcerogenic index. Marked reduction of ulcerogenic index and comparable analgesic, anti-inflammatory activities were obtained in all cases as compared to KC. Among synthesized prodrugs, viz. AR-11, AR-19 and AR-20 showed excellent pharmacological response and encouraging hydrolysis rate both in SIF and in 80% human plasma. Prodrugs with increased aliphatic side chain length or introduction of aromatic substituent showed enhanced partition coefficient but diminished dissolution and hydrolysis rates. Such prodrugs can be considered for sustained release purpose.