Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1.
Design, synthesis, and discovery of 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and related derivatives as novel inhibitors of mPGES-1.
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DOI：
10.1016/j.bmcl.2018.02.011
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发表时间：
2018-03-01
影响因子：
2.7
通讯作者：
Zhan CG
中科院分区：
文献类型：
--
作者：
Ding K;Zhou Z;Zhou S;Yuan Y;Kim K;Zhang T;Zheng X;Zheng F;Zhan CG
人mPGES-1已成为探索下一代抗炎药物的有希望的靶点，因为预期选择性mPGES-1抑制剂有区别地抑制诱导的PGE 2的产生，而不阻断其他前列腺素类（包括稳态PGE 2）的正常生物合成。因此，这种治疗方法被认为减少了与应用传统非甾体抗炎药（tNSAID）和选择性考克斯-2抑制剂（coxib）相关的不良反应。通过基于结构的虚拟筛选，以（Z）-5-亚苄基-2-亚氨基噻唑烷-4-酮为骨架的化合物为先导，合理设计新型抑制剂。此外，我们还进一步设计、合成了5-（（1，3-二苯基-1H-吡唑-4-基）亚甲基）嘧啶-2，4，6（1H，3 H，5 H）-三酮及其结构相关的衍生物，并对其体外抑制活性进行了评价。根据体外活性测定，许多这些化合物能够抑制人mPGES-1，对mPGES-1的选择性超过对考克斯同工酶的选择性。合理的分子设计，随后的合成和体外活性测定的效力和选择性的评估，导致了一组新的，有效的和选择性的mPGES-1抑制剂的发现。
Human mPGES-1 has emerged as a promising target in exploring a next generation of anti-inflammatory drugs, as selective mPGES-1 inhibitors are expected to discriminatively suppress the production of induced PGE2 without blocking the normal biosynthesis of other prostanoids including homeostatic PGE2. Therefore, this therapeutic approach is believed to reduce the adverse effects associated with the application of traditional non-steroidal anti-inflammatory drugs (tNSAIDs) and selective COX-2 inhibitors (coxibs). Identified from structure-based virtue screening, the compound with (Z)-5-benzylidene-2-iminothiazolidin-4-one scaffold was used as lead in rational design of novel inhibitors. Besides, we further designed, synthesized, and evaluated 5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones and structurally related derivatives for their in vitro inhibitory activities. According to in vitro activity assays, a number of these compounds were capable of inhibiting human mPGES-1, with the desirable selectivity for mPGES-1 over COX isozymes. Rational molecular design, followed by synthesis and in vitro activity assays for evaluating both the potency and selectivity, has led to the discovery of a set of novel, potent and selective mPGES-1 inhibitors.
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影响因子：
6.7
作者：
Ragab, Fatma A.;Gawad, Nagwa M. Abdel;Said, Mona F.
通讯作者：
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影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
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影响因子：
2.7
作者：
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3.5
作者：
Hamza, Adel;Zhao, Xinyun;Tong, Min;Tai, Hsin-Hsiung;Zhan, Chang-Guo
通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
Zhan, Chang-Guo