As a key rate-limiting enzyme in the synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1-pyrazolo[3,4-]pyridine scaffold was identified as an DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1-pyrrolo[2,3-]pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (, which was found to be the most promising and drug-like compound with potent inhibitory activity against DHODH (IC = 173.4 nM). Compound demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, exerted better therapeutic effects on ulcerative colitis than DHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, is a promising DHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.
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Article Synopsis
- The study investigates the role of ferroptosis, a type of cell death, in liver damage during sepsis, an illness caused by infection.
- Researchers used cecal ligation and puncture (CLP) to induce sepsis in mice and then analyzed liver tissue for changes, including levels of specific enzymes and oxidative stress markers.
- Results showed that inhibiting ferroptosis can reduce liver injury in septic mice, and knocking down lipocalin-2 (LCN2) helps protect against this damage by lowering oxidative stress.
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