Mycophenolate Mofetil Cellcept

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: Late 1980s (Syntex, now Roche); Year of introduction: 1995; Drug category: Immunosuppressant; Main uses Prevention of organ transplant rejection and treatment of lupus nephropathy; Related drugs: Azathioprine (Imuran).

Mycophenolate mofetil is an immunosuppressant indicated for the prevention of kidney, liver, heart, and lung transplant rejection, as well as for the treatment of inflammation of the kidney caused by systemic lupus erythematosus, an autoimmune disease.1

The development of mycophenolate mofetil was based on the observation by Anthony Allison and Elsie Eugui that certain inherited enzyme deficiencies in purine biosynthesis leading to RNA and DNA dramatically affect the immune response.

One such enzyme is inosine-5'-mono-phosphate dehydrogenase (IMPDH), which is involved in the synthesis of guanosine nucleotides, essential building blocks for RNA and DNA. Allison speculated that inhibition of this enzyme could lead to immunosuppression, because B- and T-lymphocytes are critically dependent on this pathway for proliferation, whereas other cells have alternative paths.

A series of known IMPDH inhibitors were tested and mycophenolic acid (MA), a fungal fermentation product, was identified as the most potent immunosuppressant. The mode of binding of this compound to the target enzyme is depicted in the panels below; Panel A shows the entire enzyme while Panel B gives a close-up view of the drug (shown in red) in the binding site.2 Detailed studies revealed that in addition to inhibiting B- and T-cell proliferation, MA also suppresses antibody formation by B-lymphocytes and the recruitment of lymphocytes and monocytes into the grafted organ, leading to potent immunosuppression. It was also shown to be more lymphocyte specific than its predecessor, azathioprine (see page 122), causing less bone marrow suppression. The oral bioavailability of mycophenolic acid was greatly improved by conversion to its 2-morpholinoethyl ester, mycophenolate mofetil. Cleavage of the ester moiety (shown in red) in the body leads to the active drug, mycophenolic acid.3

Mycophenolate mofetil was introduced in 1995 as CellCept. It is now widely used because of its effectiveness and relative safety, and has annual sales of over $1 billion.

Panel B

1. BioDrugs 1999, 12, 363-410; 2. Cell 1996, 85, 921-930 (1JR1); 3. Transplantation 2005, 80, S181-190; Refs. p. 173

Panel B

1. BioDrugs 1999, 12, 363-410; 2. Cell 1996, 85, 921-930 (1JR1); 3. Transplantation 2005, 80, S181-190; Refs. p. 173

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