Inosine 5 -monophosphate dehydrogenase inhibitors

C9H12N2O5S 260.27 Inosine monophosphate dehydrogenase inhibitor. Antineoplastic agent showing broad-spectrum antiviral activity. Light yellow needles (EtOH/EtOAc). Mp 145-146°. [a] -9 (c, 0.5 in EtOH). Log P -2.73 (calc). 

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. 

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... 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

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],... 

In inosine monophosphate dehydrogenase, the monovalent metal ion accelerates the hydride transfer step of the reaction with apparently few other effects on the enzyme structure. Probably the monovalent cation is involved in helping position the nicotinamide cofactor. The active site and location of the potassium ion are shown in Figure 2. Mycophenolic acid in this diagram is an inhibitor that is thought to lock inosine monophosphate into the active site, as shown. Note the large distance between the inhibitor (in the active site) and the K+. 

Figure 2 The active site of inosine monophosphate dehydrogenase, drawn from PDB file IJRl. This shows the inhibitor mycophenolic acid at the active site, stacking against PLP. The K+ site is distant from the active site...

Base-induced (KH or /-BuOK) cyclizations of o-alkynylanilines were utilized to prepare 2-substituted indoles and poly-substituted indoles. For example, treatment of alkynes 86 with KH gave the corresponding indoles 87 <03T1571>. Similar base-mediated cyclizations and related indole syntheses were utilized to prepare indole inhibitors of 5 -inosine monophosphate dehydrogenase <03BMCL1273>. Moreover, base-induced cyclizations of arylacetonitriles with oxalic acid bis(imidoyl)chlorides provide a route to 2-alkylidene-3-iminoindoles <03CEJ3951>. 

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). 

B Mycophenoiate mofetil and other antiproiiferative agents fre-quentiy cause leukopenia and thrombocytopenia. Mycophenoiic acid (active form of mycophenoiate mofetil) inhibits the enzyme inosine monophosphate dehydrogenase, the key enzyme in the de novo pathway for purine biosynthesis. Activated T-lymphocytes cannot use the salvage pathway for purine biosynthesis, and therefore are sensitive to the effects of mycophenoiic acid. The caicineurin inhibitors, IL-2 receptor antagonists, and corticosteroids do not cause bone marrow suppression. 

This in situ generation of enamines and subsequent Heck cyclization to afford indoles has been adopted by several groups for the synthesis of indoles (and azaindoles) from 2-chloroanilines [337], tricyclic inhibitors of 5 -inosine monophosphate dehydrogenase [145], medium-ring fused indoles [338], and tetrahydrocarbazole in an Organic Synthesis preparation [339]. Some mechanistic insights have been offered [340]. The use of aryl-propynamides and rV-alkynyl-2-haloanilides under Heck conditions affords oxindoles [341] and 2-aminomdoles [342], respectively. An example of the latter is illustrated for 323 to 324. 

Mofetil mycophenolate is a noncompetitive, reversible, inhibitor of inosine monophosphate dehydrogenase that inhibits lymphocyte proliferation. The use of mofetil mycophenolate with concomitant CsA dose reduction or withdrawal has showed to be safe in terms of acute rejection and in many times to induce rapid and significant improvements in renal function and hemodynamics in renal transplant recipients with stable or impaired renal function [337-340] and stable hver or heart transplant recipients with renal dysfunction [341-343]. David-Neto et al retrospectively analyzed a group of 13 renal transplanted children with biopsy showing chronic transplant nephropathy whom had CsA dose reduced or withdrawn and azathiopiine switched to mofetil mycophenolate. Six months after the introduction of mofetil mycophenolate median serum creatinine decreased from values of 2.2 mg/dl to... 

Mechanism of action This drug is rapidly converted into mycophenolic acid, which inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of purine synthesis. This action suppresses both B and T lymphocyte activation. Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the alternative salvage pathway for purine synthesis. 

Two further natural product-derived immunosuppressants have been introduced recently, mycophenclate scdium and everclimus (Fig. 1.7) (44). The active principle of both mycophenolate sodium and an earlier introduced form, mycophenolate mofetil (a morpholinoethyl derivative), is mycophenolic acid, obtained from several Penicillium sp. This compound is a reversible inhibitor of inosine monophosphate dehydrogenase, which is involved in guanosine nucleotide synthesis (80). 

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>. 

The purine synthase inhibitor mizoribine is phosphorylated to the active form mizoribine 5 -monophosphate, which selectively inhibits inosine monophosphate dehydrogenase and guanosine monophosphate synthetase. Mizoribine has been used to treat systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, and other childhood diseases. 

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