Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. box 3030, Irbid 22110, Jordan.
Faculty of Pharmacy, University of Petra, Amman 11196, Jordan.
Pharmaceuticals (Basel). 2014 Apr 14;7(4):453-63. doi: 10.3390/ph7040453.
The N-ethoxycarbonylmorpholine moiety was evaluated as a novel prodrug moiety for carboxylic acid containing drugs represented by diclofenac (1). Compound 2, the N-ethoxycarbonylmorpholine ester of diclofenac was synthesized and evaluated as a potential prodrug. The stability of the synthesized prodrug was evaluated in solutions of pH 1 and 7.4, and in plasma. The ester's half lives were found to be 8 h, 47 h and 21 min in pH 1, pH 7.4 and plasma, respectively. Equimolar doses of diclofenac sodium and its synthesized prodrug were administered orally to a group of rabbits in a crossover study to evaluate their pharmacokinetic parameters. The prodrug 2 shows a similar rate and extent of absorption as the parent drug (1). The ulcerogenicity of the prepared prodrug was evaluated and compared with the parent drug. The prodrug showed less ulcerogenicity as detected by fewer number and smaller size of ulcers. In conclusion, the newly synthesized N-ethoxycarbonylmorpholine ester of diclofenac prodrug showed appropriate stability properties at different pHs, similar pharmacokinetic profile, and much less ulcerogenecity at the GIT compared to the parent drug diclofenac.
N-乙氧羰基吗啉作为一种新型前药基团，用于评估含羧酸的药物（以双氯芬酸（1）为例）。合成了双氯芬酸的 N-乙氧羰基吗啉酯（2），并将其评估为一种有潜力的前药。在 pH 值为 1 和 7.4 的溶液中和血浆中评估了合成前药的稳定性。酯的半衰期分别为 8 小时、47 小时和 21 分钟，在 pH 值为 1、pH 值为 7.4 和血浆中。在一项交叉研究中，给一组兔子口服给予等摩尔剂量的双氯芬酸钠及其合成前药，以评估其药代动力学参数。前药 2 显示出与母体药物（1）相似的吸收速度和程度。评估了制备的前药的致溃疡作用，并与母体药物进行了比较。前药显示出较低的致溃疡作用，溃疡数量较少且较小。总之，与母体药物双氯芬酸相比，新合成的 N-乙氧羰基吗啉双氯芬酸前药在不同 pH 值下具有适当的稳定性、相似的药代动力学特征和在胃肠道中较低的致溃疡作用。
