Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Laboratório de Farmacologia da Dor e Inflamação, ICB, UFRJ, Rio de Janeiro, Brazil.
Chem Biol Drug Des. 2018 Feb;91(2):391-397. doi: 10.1111/cbdd.13085. Epub 2017 Sep 10.
Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a-d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC = 4.45 μm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration.
蛋白激酶是开发新型治疗药物治疗多种慢性疾病的有吸引力的治疗靶点。一些现有的药物，如替尼类，是酪氨酸激酶抑制剂；同时，丝氨酸/苏氨酸激酶抑制剂，如丝裂原活化蛋白激酶（MAPK），仍在试图克服临床开发过程中的一个步骤中的一些问题，以成为药物。因此，在这里我们报道了新的萘基-N-酰腙衍生物的合成、体外激酶抑制谱、对接研究以及在动物模型中的抗炎谱评价。尽管所有测试的化合物（3a-d）均被表征为 p38α MAPK 抑制剂，并表现出体内抗炎作用，但 LASSBio-1824（3b）作为 p38α MAPK 抑制剂表现出最佳性能，IC 50 为 4.45μm，并且也被证明是最有前途的抗炎原型，口服后具有良好的体内抗 TNF-α 作用。
