IMPDH inhibitor

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

Inosine 5 -Monophosphate Dehydrogenase. A series of 21 known inosine 5 -monophosphate dehydrogenase (IMPDH) inhibitors was used to validate a virtual screening protocol. By application of a molecular weight filter (80 < MW < 400), 3425 compounds were extracted from an in-house reagent inventory system. Docking of these compounds into a substrate-IMPDH complex 3D structure was performed with the program FlexX three... 

Selenazofurin (158), selenophenfurin (159), and dinucleosides such as 160 (Fig. 10), are potent inosine monophosphate dehydrogenase (IMPDH) inhibitors and have pronounced antitumor activity in animals and broad spectrum antiviral as well as maturation-inducing activities [262-264], The inhibitory effects of heterocyclic organoselenium compounds such as ebselen and some of its derivatives have been demonstrated on 15-LOXs [21, 265],... 

When jV-protected indole-3-carboxaldehydes were allowed to react with tosylmethyl isocyanide, 3-(oxazol-5-yl)-indoles were obtained in satisfactory yields and applied to the synthesis of novel indole-based IMPDH inhibitors <02BMCL3305>. In the same context, a modified approach to 2-(JV-aryl)oxazoles employing an iminophosphorane/ isothiocyanate-mediated methodology and its application to the synthesis of the potent IMPDH inhibitor BMS-337197, was reported <020L2091>. 

Additional urea-based IMPDH inhibitors, (I) and (II), were prepared by the authors (2) and Stamos (3), respectively, and used as immunosuppressive agents following transplant procedures. 

Tli is immunosuppressive drug, which is only marketed in Japan, is a nucleoside analog. Its phosphorylated form, mizoribine-5-phosphate, is a potent inhibitor of IMPDH activity. 

Stuyver LJ, Lostia S, Patterson SE, Clark JL, Watanabe KA, Otto MJ, Pankiewicz KW (2002) Inhibitors of the IMPDH enzyme as potential anti-bovine viral diarrhoea virus agents, Antivir Chem Chemother 13 345-52... 

Pickett SD, Sherborne BS, Wilkinson T, Bennett J, Borkakoti N, Broadhurst M, Hurst D, Kilford I, McKinnell M, Jones PS. Discovery of novel low molecular weight inhibitors of IMPDH via virtual needle screening. Bioorg Med Chem Lett 2003 13 1691-4. 

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... 

A prodrug form of (56) (mycophenolicacid), a noncompetitive inhibitor of IMPDH, is approved for human therapeutic use as an im-... 

The structure of hamster IMPDH in complex with IMP and (56)was solved at Vertex in the mid-1990s (129). This allowed the visualization of a covalent intermediate, in which a cysteine thiol from the enzyme adds to C2 of the purine ring of the nucleotide substrate. An analogous covalent adduct is postulated to be a key catalytic intermediate during normal turnover (130). The structure was a key tool in the discovery of (57)(VX-497, merimepodip),a novel potent inhibitor of human IMPDH suitable for oral administration (131). 

An experimental screen of a diverse library of commercially available compounds for inhibitors of IMPDH identified molecules with the phenyl, phenyloxazole urea scaffold (58) as weak inhibitors. Through use of the compu-... 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

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. 

Inosine monophosphate dehydrogenase (IMPDH) is an enzyme in the de novo synthetic pathway of guanosine nucleotides. Pitts et al. have identified several series of novel triazine inhibitors of the enzyme IMPDH II. These compounds demonstrate that the urea or diamide isosteres can be replaced effectively by heterocycles <2002BML2137>. 

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