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Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-09-10 , DOI: 10.1111/cbdd.13085 Rosana H. C. N. Freitas 1 , Natália M. Cordeiro 2 , Patrícia R. Carvalho 2 , Marina A. Alves 1 , Isabella A. Guedes 3 , Tayna S. Valerio 2 , Laurent E. Dardenne 3 , Lídia M. Lima 1 , Eliezer J. Barreiro 1 , Patrícia D. Fernandes 2 , Carlos A. M. Fraga 1
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2017-09-10 , DOI: 10.1111/cbdd.13085 Rosana H. C. N. Freitas 1 , Natália M. Cordeiro 2 , Patrícia R. Carvalho 2 , Marina A. Alves 1 , Isabella A. Guedes 3 , Tayna S. Valerio 2 , Laurent E. Dardenne 3 , Lídia M. Lima 1 , Eliezer J. Barreiro 1 , Patrícia D. Fernandes 2 , Carlos A. M. Fraga 1
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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 IC50 = 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.
中文翻译：
发现具有体内抗炎和抗TNF-α活性的萘基-N-酰基hydrp38αMAPK抑制剂
蛋白激酶构成了开发用于治疗不同慢性疾病的新原型的有吸引力的治疗靶标。几种可用的药物，如替尼类，是酪氨酸激酶抑制剂。同时，丝氨酸/苏氨酸激酶的抑制剂，例如有丝分裂原激活的蛋白激酶（MAPK），仍在试图克服成为药物的临床开发步骤之一中的某些问题。因此，在这里我们报道了使用动物模型对新萘基-N-酰基hydr衍生物的合成，体外激酶抑制谱，对接研究以及抗炎谱的评价。尽管所有测试化合物（3a–d）均已表征为p38αMAPK抑制剂并显示出体内抗炎作用，但LASSBio-1824（3b）呈现为p38αMAPK抑制剂的最佳性能，具有IC 50 = 4.45μ米，并且还证明是最有前途的抗炎原型，与口服给药后良好的体内抗TNF-α的轮廓。
更新日期：2017-09-10
中文翻译：
发现具有体内抗炎和抗TNF-α活性的萘基-N-酰基hydrp38αMAPK抑制剂
蛋白激酶构成了开发用于治疗不同慢性疾病的新原型的有吸引力的治疗靶标。几种可用的药物，如替尼类，是酪氨酸激酶抑制剂。同时，丝氨酸/苏氨酸激酶的抑制剂，例如有丝分裂原激活的蛋白激酶（MAPK），仍在试图克服成为药物的临床开发步骤之一中的某些问题。因此，在这里我们报道了使用动物模型对新萘基-N-酰基hydr衍生物的合成，体外激酶抑制谱，对接研究以及抗炎谱的评价。尽管所有测试化合物（3a–d）均已表征为p38αMAPK抑制剂并显示出体内抗炎作用，但LASSBio-1824（3b）呈现为p38αMAPK抑制剂的最佳性能，具有IC 50 = 4.45μ米，并且还证明是最有前途的抗炎原型，与口服给药后良好的体内抗TNF-α的轮廓。
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