Rashad Aya Y, Daabees Hoda G, Elagawany Mohamed, Shahin Mohamed, Abdel Moneim Ahmed E, Rostom Sherif A F
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, El-Buhaira 22516, Egypt.
Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Damanhour University, Damanhour, El-Buhaira 22516, Egypt.
Bioorg Chem. 2023 Jun;135:106502. doi: 10.1016/j.bioorg.2023.106502. Epub 2023 Mar 31.
Treatment of gout involves two basic approaches: reducing the serum uric acid mainly by xanthine oxidase inhibitors (XOIs) and alleviating the intensity of the accompanying acute arthritic inflammation using non-steroidal anti-inflammatory drugs (NSAIDs). Febuxostat (FEB) is the first non-purine XOI approved for the treatment of hyperuricemia and gout. The present study aims at combining the hypouricemic effect of FEB and the anti-inflammatory (AI) properties of NSAIDs in a single entity by adopting the "mutual prodrug" approach. Accordingly, a series of seven ester prodrugs comprising basically FEB together with different NSAIDs namely, diclofenac (4), ibuprofen (5), ketoprofen (6), indomethacin (7), naproxen (8), ketorolac (9) and etodolac (10) was synthesized. All the investigated seven prodrugs (4-10) were equipotent or even superior to their corresponding parent drugs in the hypouricemic and AI activities, together with a gastrointestinal (GI) safety profile. Among this series, the prodrug FEB-DIC (4) showed excellent dual in vivo hypouricemic and anti-inflammatory activity (43.60 % and 15.96 %, respectively) when compared to the parent drugs FEB and diclofenac (36.82 % and 12.10 %, respectively) and its physical mixture (37.28 % and 12.41 %, respectively). Investigation of the in vitro chemical stability and hydrolysis of the prodrug (4) in aqueous and biological samples using a developed HPLC method confirmed its stability in various pHs, whereas rapid hydrolysis to the parent drugs in liver homogenate and human plasma was proven. Finally, it is concluded that the mutual prodrug approach could be successfully used in drug design and development for overcoming undesirable difficulties without losing the desired activities of the parent drugs.
主要通过黄嘌呤氧化酶抑制剂（XOIs）降低血清尿酸，并使用非甾体抗炎药（NSAIDs）减轻伴随的急性关节炎炎症的强度。非布司他（FEB）是首个被批准用于治疗高尿酸血症和痛风的非嘌呤类XOIs。本研究旨在通过采用“相互前药”方法，将FEB的降尿酸作用和NSAIDs的抗炎（AI）特性结合在一个单一实体中。因此，合成了一系列七种酯前药，基本上由FEB与不同的NSAIDs组成，即双氯芬酸（4）、布洛芬（5）、酮洛芬（6）、吲哚美辛（7）、萘普生（8）、酮咯酸（9）和依托度酸（10）。所有研究的七种前药（4 - 10）在降尿酸和AI活性方面与其相应的母体药物相当甚至更优，同时具有胃肠道（GI）安全性。在这个系列中，前药FEB - DIC（4）与母体药物FEB和双氯芬酸（分别为36.82%和12.10%）及其物理混合物（分别为37.28%和12.41%）相比，在体内表现出优异的双重降尿酸和抗炎活性（分别为43.60%和15.96%）。使用开发的高效液相色谱法对前药（4）在水性和生物样品中的体外化学稳定性和水解进行研究，证实了其在各种pH值下的稳定性，而在肝匀浆和人血浆中能快速水解为母体药物。最后得出结论，相互前药方法可成功用于药物设计和开发，以克服不良困难，同时不丧失母体药物的期望活性。
