Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , Campus de Cartuja s/n , 18071 Granada , Spain.
Hospital Universitario de Canarias, Universidad La Laguna & Center for Rare Diseases (CIBERER) , 38320 Tenerife , Spain.
J Med Chem. 2018 Aug 23;61(16):7144-7167. doi: 10.1021/acs.jmedchem.8b00399. Epub 2018 Aug 6.
Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.
原发性高草酸尿症 1 型（PH1）是一种罕见的危及生命的遗传性疾病，与乙醛酸代谢有关，其特征是草酸钙晶体的积累。目前的治疗方法包括肝和/或肾移植，这些手术具有显著的发病率和死亡率，并需要长期免疫抑制。因此，迫切需要一种药物治疗。我们在这里介绍了水杨酸衍生物作为能够在低微摩尔范围内降低高草酸尿症肝细胞中草酸盐分泌的药物的前所未有的活性，这意味着它们可能用于治疗 PH1。尽管这种表型活性与乙醛酸氧化酶（GO）抑制的相关性仍有待验证，但这里描述的大多数水杨酸都是 GO 抑制剂，IC 值低至 3 μM。使用计算机模拟方法研究了水杨酸在 GO 内的结合模式，并建立了初步的构效关系。我们化合物的类药性结构和易于合成使它们成为结构优化的有前途的候选药物。
