Thienopyrimidinone derivative

During the first years of COVID‐19 pandemic, X‐ray structures of the coronavirus drug targets were acquired at an unprecedented rate, giving hundreds of PDB depositions in less than a year. The main protease (Mpro) of severe acute respiratory syndrome‐related coronavirus 2 (SARS‐CoV‐2) is the primary validated target of direct‐acting antivirals. The selection of the optimal ensemble of structures of Mpro for the docking‐driven virtual screening campaign was thus non‐trivial and required a systematic and automated approach. Here we report a semi‐automated active site RMSD based procedure of ensemble selection from the SARS‐CoV‐2 Mpro crystallographic data and virtual screening of its inhibitors. The procedure was compared with other approaches to ensemble selection and validated with the help of hand‐picked and peer‐reviewed activity‐annotated libraries. Prospective virtual screening of non‐covalent Mpro inhibitors resulted in a new chemotype of thienopyrimidinone derivatives with experimentally confirmed enzyme inhibition.

Urate Transporter 1 (URAT1) plays a crucial role in uric acid transport, making it an attractive target for the treatment of gout and hyperuricemia. As a representative URAT1 inhibitor, Lesinurad treat gout by promoting the uric acid excretion. However, its lower in vitro and in vivo activity should be highly attracted attention. Herein, the bioisosterism, molecular hybridization and scaffold hopping strategies were exploited to modify all the structural components of Lesinurad and finally thirty novel compounds bearing thienopyrimidinone or pyridine core were obtained. Most of the compounds displayed certain URAT1 inhibitory activity in vitro. Among them, thienopyrimidinones 6 (IC₅₀ = 7.68 μM), 10 (IC₅₀ = 7.56 μM), 14 (IC₅₀ = 7.31 μM) and 15 (IC₅₀ = 7.90 μM) showed slightly better potency than positive control Lesinurad (IC₅₀ = 9.38 μM). Notably, 10 also displayed inhibitory activity (IC₅₀ = 55.96 μM) against GLUT9. Additionally, in vivo serum uric acid (SUA)-lowering experiments were performed on some representative compounds and it was revealed that all the selected compounds could decrease the SUA level in mice, of which the decrease rate of SUA was 73.29% for the most promising compound 10, significantly greater than that of Lesinurad (26.89%). Meanwhile, the preliminary SARs based on the URAT1 inhibitory activity were discussed in detail, which pointed out the direction for further structural optimization. Overall, the thienopyrimidinone and pyridine are prospective skeletons for the developing novel URAT1 inhibitors with considerable potential for optimization.