Awasthi Archana, Raju Mantripragada Bhagavan, Rahman Md Azizur
Department of Pharmaceutical Chemistry, Sri Venkateshwara College of Pharmacy, Madhapur, Hyderabad, Telangana, India.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Integral University, Lucknow, Uttar Pradesh, India.
Med Chem. 2021;17(6):555-575. doi: 10.2174/1573406416666200227122849.
The inflammatory process is one of the mechanisms by which our body upholds us from pathogens such as parasites, bacteria, viruses, and other harmful microorganisms. Inflammatory stimuli activate many intracellular signaling pathways such as the nuclear factor-kB (NF-kB) pathway and three mitogen-activated protein kinase (MAPK) pathways, which are mediated through extracellular-signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38. The p38 has evolved as an enticing target in treating many persistent inflammatory diseases. Hence, designing novel p38 inhibitors targeting MAPK pathways has acquired significance.
Peruse to identify the lead target to discover novel p38MAPK inhibitors with different scaffolds having improved selectivity over the prototype drugs.
Structure and the binding sites of p38MAPK were focused. Various scaffolds designed for inhibition and the molecules which have entered the clinical trials are discussed.
This review aspires to present the available information on the structure and the 3D binding sites of p38MAPK, various scaffolds designed for imidazole, urea, benzamide, azoles, quinoxaline, chromone, ketone as a potent p38MAPK inhibitors and their SAR studies and the molecules which have entered the clinical trials.
The development of successful selective p38MAPK inhibitors in inflammatory diseases is in progress despite all challenges. It was speculated that p38MAPK also plays an important role in treating diseases such as neuroinflammation, arterial inflammation, vascular inflammation, cancer and so on, which are posing the world with treatment challenges. In this review, clinical trials of drugs are discussed related to inflammatory and its related diseases. Research is in progress to design and develop novel p38MAPK inhibitors with minimal side effects.
炎症过程是我们身体抵御寄生虫、细菌、病毒和其他有害微生物等病原体的机制之一。炎症刺激激活许多细胞内信号通路，如核因子-κB（NF-κB）通路和三种丝裂原活化蛋白激酶（MAPK）通路，这些通路由细胞外信号调节激酶（ERK）、c-Jun氨基末端激酶（JNK）和p38介导。p38已成为治疗许多持续性炎症疾病的诱人靶点。因此，设计针对MAPK通路的新型p38抑制剂具有重要意义。
旨在确定先导靶点，以发现具有不同骨架且对原型药物具有更高选择性的新型p38MAPK抑制剂。
聚焦于p38MAPK的结构和结合位点。讨论了为抑制作用设计的各种骨架以及已进入临床试验的分子。
本综述旨在介绍有关p38MAPK的结构和三维结合位点、为咪唑、尿素、苯甲酰胺、唑类、喹喔啉、色酮、酮设计的作为有效p38MAPK抑制剂的各种骨架及其构效关系研究以及已进入临床试验的分子的现有信息。
尽管面临所有挑战，但针对炎症性疾病的成功选择性p38MAPK抑制剂的开发仍在进行中。据推测，p38MAPK在治疗神经炎症、动脉炎症、血管炎症、癌症等疾病中也起着重要作用，这些疾病给全球治疗带来了挑战。在本综述中，讨论了与炎症及其相关疾病相关的药物临床试验。目前正在进行研究，以设计和开发副作用最小的新型p38MAPK抑制剂。
