Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template
Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template
复制标题
DOI：
10.1016/s0006-291x(02)02996-0
复制
发表时间：
2003-01-31
影响因子：
3.1
通讯作者：
Sudarsanam, V
中科院分区：
文献类型：
--
作者：
Pillai, AD;Rathod, PD;Sudarsanam, V
噻吩是一种π过量的五元杂环，由于其作为药物分子支架的治疗作用，引入噻吩结构的化合物吸引了大量的研究兴趣。我们报告的合成和药理学评价噻吩取代4-甲磺酰基苯甲酰基部分在第五位的环，作为可能的抗炎铅候选人。当在角叉菜胶诱导的大鼠爪水肿（急性体内模型）中筛选抗炎活性时，芳基磺酰基甲基噻吩类似物AP 29、AP 82和AP 37在100 mg/kg体重的剂量水平下与I.o.相比表现出中等至良好的活性。在5天福尔马林诱导的大鼠爪水肿（一种慢性疾病体内抗炎模型）中，与治疗剂量的罗非考昔、伊莱克斯和地塞米松相比，候选物AP 29、AP 82和AP 37在100 mg/kg体重的剂量水平下在第5天分别抑制疾病进展53%、34%和65%，所述治疗剂量提供53.8%的保护。81.5%和81.5%。用吡啶模板3，5-二甲基-4-甲氧基-2-吡啶基官能团取代AP 82中的4-甲磺酰基苯甲酰基部分，产生了AP 84，其在急性模型中活性较低，但在慢性模型中，在第1天和第5天分别提供了54%和75%的保护。提出了AP 84的双重作用机制，AP 84是一种非甾体药物，与甾体地塞米松相比具有显著的活性。这些结果开辟了新的途径，在设计新的抗炎药物作为双重抑制剂的结合吡啶模板作为药效团的一部分。(C)2003 Elsevier Science（美国）。All rights reserved.
Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic ill vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore. (C) 2003 Elsevier Science (USA). All rights reserved.