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].

References:
[1] Yao H W, Li J, Chen J Q, et al.  A 771726, the active metabolite of leflunomide, inhibits TNF-α and IL-1 from Kupffer cells[J]. Inflammation, 2004, 28(2): 97-103.
[2] Breedveld F C, Dayer J M.  Leflunomide: mode of action in the treatment of rheumatoid arthritis[J]. Annals of the rheumatic diseases, 2000, 59(11): 841-849.
[3] Burger D, Begué‐Pastor N, Benavent S, et al.  The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E2, matrix metalloproteinase 1 and interleukin 6 in human fibroblast‐like synoviocytes[J]. Rheumatology, 2003, 42(1): 89-96.
[4] Davis J P, Cain G A, Pitts W J, et al.  The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase[J]. Biochemistry, 1996, 35(4): 1270-1273.