Ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) negatively regulates the anti-cancer Stimulator of Interferon Genes (STING) pathway. We discovered that 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one derivatives possessed inhibitory activities on ENPP1. A structure–activity relationship (SAR) study led to the identification of 46 and 23 as potent ENPP1 inhibitors. Also, compounds 46 and 23 possessed high microsomal stabilities in human, rat, and mouse liver microsome. Additionally, CYPs (1A2, 2C9, 2C19, 2D6, and 3A4) were not inhibited by 46 and 23. Molecular dynamics simulations provided an insight of binding modes between ENPP1 and compounds (46 and 23).

外核苷酸焦磷酸酶/磷酸二酯酶-1 (ENPP1) 负调控干扰素基因的抗癌刺激物 (STING) 通路。我们发现 3,4-dihydropyrimido[4,5- d ]pyrimidin-2(1 H )-one 和 3,4-dihydropyrido[2,3 - d ]pyrimidin-2( 1H )-one 衍生物具有抑制活性在 ENPP1 上。一项构效关系 (SAR) 研究将46和 23 鉴定为有效的 ENPP1 抑制剂。此外，化合物 46 和23在人、大鼠和小鼠肝微粒体中具有高度的微粒体稳定性。此外，CYP（1A2、2C9、2C19、2D6 和 3A4）不受 46 和23的抑制. 分子动力学模拟提供了对 ENPP1 和化合物之间结合模式的了解（46 和23）。