Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada T6G 2N8.
Bioorg Med Chem Lett. 2010 Feb 15;20(4):1324-9. doi: 10.1016/j.bmcl.2010.01.014. Epub 2010 Jan 11.
A new group of hybrid nitric oxide (NO) releasing anti-inflammatory (AI) coxib prodrugs (NO-coxibs) wherein the para-tolyl moiety present in celecoxib was replaced by a N-(4-nitrooxybutyl)piperidyl 15a-b, or N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl 17a-b, NO-donor moiety was synthesized. All compounds released a low amount of NO upon incubation with phosphate buffered saline (PBS) at pH 7.4 (2.4-5.8% range). In comparison, the percentage NO released was higher (3.1-8.4% range) when these nitrate prodrugs were incubated in the presence of L-cysteine. In vitro COX-1/COX-2 isozyme inhibition studies showed this group of compounds are moderately more potent, and hence selective, inhibitors of the COX-2 relative to the COX-1 enzyme. AI structure-activity relationship data acquired showed that compounds having a MeSO2 COX-2 pharmacophore exhibited superior AI activity compared to analogs having a H2NSO2 substituent. Compounds having a MeSO2 COX-2 pharmacophore in conjunction with a N-(4-nitrooxybutyl)piperidyl (ED50=132.4 mg/kg po), or a N-(4-nitrooxybutyl)-1,2,3,6-tetrahydropyridyl (ED50=118.4 mg/kg po), moiety exhibited an AI potency profile that is similar to aspirin (ED50=128.7 mg/kg po) but lower than ibuprofen (ED50=67.4 mg/kg po).
一组新的混合一氧化氮（NO）释放抗炎（AI）昔布前药（NO-coxibs），其中塞来昔布中存在的对甲苯基部分被 N-（4-硝基氧丁基）哌啶 15a-b 或 N-（4-硝基氧丁基）-1,2,3,6-四氢吡啶 17a-b，NO 供体部分取代。所有化合物在磷酸盐缓冲盐水（PBS）pH7.4 孵育时释放少量的 NO（2.4-5.8%范围）。相比之下，当这些硝酸盐前药在 L-半胱氨酸存在下孵育时，释放的 NO 百分比更高（3.1-8.4%范围）。体外 COX-1/COX-2 同工酶抑制研究表明，与 COX-1 酶相比，该化合物组对 COX-2 的抑制作用更强，因此选择性更高。获得的 AI 构效关系数据表明，具有 MeSO2 COX-2 药效团的化合物比具有 H2NSO2 取代基的类似物具有更好的 AI 活性。具有 MeSO2 COX-2 药效团的化合物与 N-（4-硝基氧丁基）哌啶（ED50=132.4mg/kg po）或 N-（4-硝基氧丁基）-1,2,3,6-四氢吡啶（ED50=118.4mg/kg po）部分结合，表现出与阿司匹林（ED50=128.7mg/kg po）相似但低于布洛芬（ED50=67.4mg/kg po）的 AI 效力谱。
