Intramolecular hydrogen bond interruption and scaffold hopping of TMC-5 led to 2-(4-alkoxy-3-cyanophenyl)pyrimidine-4/5-carboxylic acids and 6-(4-alkoxy-3-cyanophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-ones as potent pyrimidine-based xanthine oxid
Intramolecular hydrogen bond interruption and scaffold hopping of TMC-5 led to 2-(4-alkoxy-3-cyanophenyl)pyrimidine-4/5-carboxylic acids and 6-(4-alkoxy-3-cyanophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-ones as potent pyrimidine-based xanthine oxid
复制标题
TMC-5 的分子内氢键中断和支架跳跃生成 2-(4-烷氧基-3-氰基苯基)嘧啶-4/5-羧酸和 6-(4-烷氧基-3-氰基苯基)-1,2-二氢
DOI：
10.1016/j.ejmech.2021.114086
复制
发表时间：
2022
影响因子：
6.7
通讯作者：
Shaojie Wang
中科院分区：
文献类型：
--
作者：
Jiaxing Zhao;Qing Mao;Fengwei Lin;Bing Zhang;Ming Sun;Tingjian Zhang;Shaojie Wang
最近报道了许多具有不同化学型的基于嘧啶的黄嘌呤氧化酶（XO）抑制剂。我们之前的研究表明，2-(4-烷氧基-3-氰基)苯基-6-亚氨基-1,6-二氢嘧啶-5-羧酸衍生物表现出显着的XO抑制效力。值得注意的是，可以观察到氨基和羧基之间形成的分子内氢键（IMHB）。为了扩大构效关系（SAR）并获得潜在的基于嘧啶的 XO 抑制剂，对这些化合物进行了 IMHB 中断和支架跳跃，设计了 2-(4-烷氧基-3-氰基苯基)嘧啶-4/5-羧酸 (11a-11nand15a-15j) 和6-(4-烷氧基-3-氰基苯基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(19a-19j)。其中，化合物19a（IC50=0.039μM）被认为是最有前途的化合物，其体外抑制效力明显高于别嘌呤醇（IC50=7.590μM），并且与非布索坦（IC50=0.028μM）相当。 SAR 分析表明，通过去除氨基来中断 IMHB 可能会损害 XO 的抑制效力；嘧啶-4-羧酸部分比嘧啶-5-羧酸部分更有利于XO抑制效力。此外，酶动力学研究表明，化合物11a、15a和19a充当XO的混合型抑制剂，并且去除6位氨基导致对游离酶的亲和力减弱，但与酶-底物复合物的结合增强。分子模型为本研究中观察到的 SAR 提供了合理的解释。此外，体内低尿酸血症效应表明，化合物 15a 和 19a 在口服剂量 10 mg/kg 时可有效降低血清尿酸水平，其中 19 表现出比 15a 更强的作用。因此，我们的研究证明6-(4-烷氧基-3-氰基苯基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮是有效的基于嘧啶的XO抑制剂，并且化合物19a需要进一步的结构优化作为治疗高尿酸血症和痛风的潜在有效药物。
Many pyrimidine-based xanthine oxidase (XO) inhibitors with diverse chemotypes have been reported recently. Our previous study revealed that 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acid derivatives exhibited remarkable XO inhibitory potency. Notably, an intramolecular hydrogen bond (IMHB) formed between amino and carboxylic groups could be observed. With the hope to expand the structure-activity relationships (SARs) and obtain potential pyrimidine-based XO inhibitors, IMHB interruption and scaffold hopping were carried out on these compounds to design 2-(4-alkoxy-3-cyanophenyl)pyrimidine-4/5-carboxylic acids (11a-11nand15a-15j) and 6-(4-alkoxy-3-cyanophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-ones (19a-19j). Among them, compound19a(IC50= 0.039 μM) was identified as the most promising compound with substantially higherin vitroinhibitory potency than allopurinol (IC50= 7.590 μM) and comparable to febuxostat (IC50= 0.028 μM). The SAR analysis revealed that interrupting the IMHB through the removal of the amino group could damage the XO inhibitory potency; pyrimidine-4-carboxylic acid moiety was more beneficial for the XO inhibitory potency than the pyrimidine-5-carboxylic acid moiety. Additionally, enzyme kinetics studies suggested that compounds11a,15aand19aacted as mixed-type inhibitors for XO and the removal of 6-position amino group resulted in a weakened affinity to the free enzyme, but an enhanced binding to the enzyme-substrate complex. Molecular modeling provided a reasonable explanation for the SARs observed in this study. Furthermore,in vivohypouricemic effects demonstrated that compounds15aand19acould effectively reduce serum uric acid levels at an oral dose of 10 mg/kg, with19ademonstrating a stronger effect than15a. Therefore, our study proved that 6-(4-alkoxy-3-cyanophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-ones were potent pyrimidine-based XO inhibitors and compound19arequired further structural optimization as a potential and efficacious agents for the treatment of hyperuricemia and gout.