SAR study of 1,2-benzisothiazole dioxide compounds that agonize HIF-2 stabilization and EPO production

Abstract

Benzisothiazole dioxide compound was reported to agonize HIF-2 stabilization and improve EPO production, thus conceiving a potential strategy to treat disease with chronic hypoxia exemplified by renal anemia. Herein, on the bases of multiple molecular and cellular assays, a series of benzisothiazole derivatives have been synthesized and their structure–activity relationship was evaluated. The SAR and molecular docking studies have revealed the structural insights on the rational design of HIF-2 agonist and discovered a more potential 5-bromine substituted analogue, which showed 2–4 times improvement of HIF-2 downstream gene transcriptions, including EPO production. The present results suggest the therapeutic potential of the compounds for diseases related to EPO insufficiency.