Organ transplant drugs synthesis

Mycophenolate sodium (62 Myfortic Norvatis, 2003) is an immunosuppressant drug used to prevent rejection in organ transplantation. It is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally... 

DOC organ or tissue transplantation (+/- mycophenolate +/- steroids +/- cytotoxic drugs). Tacrolimus has been used alternatively to cyclosporine in renal and liver transplants. Mycophenolate, an inhibitor of de novo synthesis of purines, has adjunctive immunosuppressant actions, permitting dose reductions of cyclosporine to limit toxicity. 

Mycophenolate mofetil (Cellcept) is an immunosuppressant approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants. Myco-phenolic acid, the active derivative of mycophenolate mofetil, inhibits the enzyme inosine monophosphatase dehydrogenase (IMPDH), thereby depleting guanosine nucleotides essential for DNA and RNA synthesis. Moreover, mycophenolic acid is a fivefold more potent inhibitor of the type 11 isoform of IMPDH found in activated B- and T-lymphocytes and thus functions as a specific inhibitor of T- and B-lymphocyte activation and proliferation. The drug also may enhance apoptosis. 

Conformational restriction played an important role in the discovery that water induces the bioactive conformation of CsA. Cyclosporin A (Sandimmune , CsA, (23.37), Fig. 23.7), is a major drug for preventing rejection of transplanted human organs and has been the subject of many synthetic, conformational and mechanism of action studies. To produce immunosuppression, CsA first binds to cyclophilin A (CyP A), a peptidyl prolyl cis-trans isomerase (PPIase), to form the CsA-CyP complex, which then binds to and inhibits calcineuiin (CaN), a calmodulin-dependent serine/threonine protein phosphatase, thereby inhibiting interleukin-2 (IL-2) synthesis. ... 

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