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A771726 is dihydroorotate dehydrogenase inhibitor.

The dihydroorotate dehydrogenase (DHODH) is a mitochondrial protein. Inhibitors of DHODH can be used to treat autoimmune diseases such as rheumatoid arthritis.

A771726, leflunomide's active metabolite, showed significantly inhibitory effect on TNF-α and IL-1 at protein and transcription levels, and reduced production of IL-1 in monocultures of Kupffer cells (KCs) [1]. A-771726 reversibly inhibited dihydroorotate dehydrogenase, the rate-limiting step in the de novo synthesis of pyrimidines. A-771726 prevented activated lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis with the IC50 values of 0.09, 3.5, and 12.5 μM for rat, mouse, and human, respectively [2]. A-771726 inhibited the activity of tyrosine kinases responsible for early T cell and B cell signaling in the G0/G1 phase of the cell cycle at higher doses [2]. A-771726 also inhibited the production of prostaglandin E2 in synoviocytes activated by TNF-α and IL-1α with the IC50 values of 7 and 3 μM, respectively. A771726 also inhibited MMP-1 and IL-6 production at concentrations >10 μM [3]. A771726 is a novel immunosuppressive compound that has been shown to be a powerful antiproliferative agent for mononuclear and T-cells. A771726 potently inhibited the activity of DHODase with the Ki of 179 ± 19 nM. A771726 was a competitive inhibitor of the ubiquinone binding site [4].

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