X-Chem Inc., 100 Beaver Street, Waltham, Massachusetts 02453, United States.
J Med Chem. 2021 May 27;64(10):6730-6744. doi: 10.1021/acs.jmedchem.0c02271. Epub 2021 May 6.
Inhibition of hydroxy acid oxidase 1 (HAO1) is a strategy to mitigate the accumulation of toxic oxalate that results from reduced activity of alanine-glyoxylate aminotransferase (AGXT) in primary hyperoxaluria 1 (PH1) patients. DNA-Encoded Chemical Library (DECL) screening provided two novel chemical series of potent HAO1 inhibitors, represented by compounds -. Compound was further optimized via various structure-activity relationship (SAR) exploration methods to , a compound with improved potency and absorption, distribution, metabolism, and excretion (ADME)/pharmacokinetic (PK) properties. Since carboxylic acid-containing compounds are often poorly permeable and have potential active glucuronide metabolites, we undertook a brief, initial exploration of acid replacements with the aim of identifying non-acid-containing HAO1 inhibitors. Structure-based drug design initiated with Compound led to the identification of a nonacid inhibitor of HAO1, , which has weaker potency and increased permeability.
抑制羟基酸氧化酶 1（HAO1）是一种减轻原发性高草酸尿症 1（PH1）患者中丙氨酸-乙醛酸转氨酶（AGXT）活性降低导致的有毒草酸盐积累的策略。DNA 编码化学文库（DECL）筛选提供了两种新型的强效 HAO1 抑制剂化学系列，分别由化合物 - 代表。通过各种构效关系（SAR）探索方法对化合物 进行了进一步优化，得到了一种具有改善的效力和吸收、分布、代谢和排泄（ADME）/药代动力学（PK）特性的化合物 。由于含有羧酸的化合物通常渗透性差，并且具有潜在的活性葡萄糖醛酸代谢物，因此我们进行了简短的初步探索，旨在寻找不含羧酸的 HAO1 抑制剂。基于结构的药物设计从化合物 开始，确定了一种非酸抑制剂 HAO1 ，其效力较弱，但渗透性增加。
