Moreira Diogo Rodrigo Magalhaes, Santos Dourivaldo Silva, Espírito Santo Renan Fernandes do, Santos Flávia Evangelista Dos, de Oliveira Filho Gevanio Bezerra, Leite Ana Cristina Lima, Soares Milena Botelho Pereira, Villarreal Cristiane Flora
Centro de Pesquisas Gonçalo Moniz, FIOCRUZ, Salvador, Bahia, Brazil.
Faculdade de Farmácia, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
Chem Biol Drug Des. 2017 Aug;90(2):297-307. doi: 10.1111/cbdd.12951. Epub 2017 Feb 22.
Chemotherapy-induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy-induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin-induced neuropathic pain, using von Frey, rota-rod and open-field tests. Except for compound 14, these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12, 15 and 16 displayed a dose-dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinski's index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy-induced neuropathic pain.
化疗引起的神经病变是一种因癌症化疗导致的致残性疼痛病症。截至目前，尚无药物可治愈化疗引起的神经病变。在本研究中，我们描述了15种噻唑烷酮类化合物的结构设计、合成、化学及药理学特性，这类化合物具有潜在的镇痛活性。新型噻唑烷酮类化合物的合成是以噻唑烷酮杂环作为主要结构药效基团，并改变与亚胺键附近苯基相连的取代基来实现的。利用von Frey、转棒和旷场试验，在奥沙利铂诱导的神经性疼痛小鼠模型中研究了这些化合物的镇痛潜力。除化合物14外，这些噻唑烷酮类化合物均表现出抗伤害感受特性且未引起运动功能障碍。噻唑烷酮类化合物12、15和16呈现出剂量依赖性抗伤害感受作用，其疗效与用于神经性疼痛的金标准药物加巴喷丁相似且效力增强。此外，化合物16的抗伤害感受活性持续时间比加巴喷丁更长。噻唑烷酮类化合物的抗伤害感受作用可被PPARγ拮抗剂GW9662阻断。主要的抗伤害感受化合物呈现出良好的类药五原则指标，预示了它们的口服生物利用度。总之，此处进行的结构设计促成了具有强效抗伤害感受活性的新化合物的鉴定，这些化合物可能对治疗化疗引起的神经性疼痛有用。
