Novel Inhibitors of Inosine Monophosphate Dehydrogenase in Patent Literature of the Last Decade (original) (raw)
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Novel inhibitors of inosine monophosphate dehydrogenase (IMPDH)
2002
Inosine monophosphate dehydrogenase (IMPDH), an NAD-dependent enzyme that controls de novo synthesis of guanine nucleotides, has received considerable interest in recent years as an important target enzyme, not only for the discovery of anticancer drugs, but also for antiviral, antiparasitic, and immunosuppressive chemotherapy. The field of IMPDH inhibitor research is highly important for providing potential therapeutics against a validated target for disease intervention. This patent review examines the chemical structures and biological activities of recently reported IMPDH inhibitors. Patent databases SciFinder and Espacenet and Delphion were used to locate patent applications that were published between January 2002 and July 2012, claiming chemical structures for use as IMPDH inhibitors. From 2002 to 2012, around 47 primary patent applications have claimed IMPDH inhibitors, which we analyzed by target and applicant. The level of newly published patent applications covering IMPDH inhibitors remains high and a diverse range of scaffolds has been claimed.
Current Medicinal Chemistry, 2004
IMP dehydrogenase, the key enzyme in de novo synthesis of purine nucleotides, is an important therapeutic target. Three inhibitors of IMP dehydrogenase reached the market; ribavirin (Rebetol) a broadspectrum antiviral agent, which in combination with interferon-α is now used for treatment of hepatitis C virus infections, mizoribine (Bredinin) and mycophenolic mofetil (CellCept) have been introduced as immunosuppressants. Numerous novel inhibitors are under development. This review describes recent progress in the development of new drugs based on inhibition of IMP dehydrogenase.
Journal of Medicinal Chemistry, 2002
Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats. Introduction. Inosine monophosphate dehydrogenase (IMPDH) is an enzyme that catalyzes the nicotinamide adenosine dinucleotide (NAD) dependent conversion of inosine 5′-monophosphate (IMP) to xanthosine 5′-monophosphate (XMP). 1 The reaction is irreversible and is the first step in the de novo synthesis of guanine nucleotides. Rapidly proliferating cells such as lymphocytes are dependent on the availability of the nucleotide pool to meet their metabolic requirement, and it is known that the activity of IMPDH is higher in proliferating cells. 2 Because of these cell requirements, IM-PDH is an attractive target for immunosuppressive, anticancer, and antiviral therapies. 3 Two isoforms of the IMPDH enzyme are known to exist: type I and type II. Human types I and II IMPDH cDNAs encode the same-size proteins (514 amino acids) and show 84% sequence identity. 4 It was initially thought that because type II expression is upregulated in neoplastic and replicating cells, it is this isoform that is responsible for cell differentiation and neoplastic transformation. 5 However, more recent work has indicated that induction of types I and II isoforms contributes significantly to the T-cell proliferation response. 6 The mechanism of IMPDH reaction has been studied in detail (Figure 1). 7 The oxidation of IMP to XMP is an irreversible reaction and utilizes NAD as the cofac
Bioorganic & Medicinal Chemistry Letters, 2003
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described. #
Bioorganic & Medicinal Chemistry, 2011
Cofactor-type inhibitors of inosine monophosphate dehydrogenase (IMPDH) that target the nicotinamide adenine dinucleotide (NAD) binding domain of the enzyme are modular in nature. They interact with the three sub-sites of the cofactor binding domain; the nicotinamide monophosphate (NMN) binding subsite (N sub-site), the adenosine monophosphate (AMP) binding sub-site (A sub-site), and the pyrophosphate binding sub-site (P sub-site or P-groove). Mycophenolic acid (MPA) shows high affinity to the N sub-site of human IMPDH mimicking NMN binding. We found that the attachment of adenosine to the MPA through variety of linkers afforded numerous mycophenolic adenine dinucleotide (MAD) analogues that inhibit the two isoforms of the human enzyme in low nanomolar to low micromolar range. An analogue 4, in which 2-ethyladenosine is attached to the mycophenolic alcohol moiety through the difluoromethylenebis(phosphonate) linker, was found to be a potent inhibitor of hIMPDH1 (K i = 5 nM), and one of the most potent, sub-micromolar inhibitor of leukemia K562 cells proliferation (IC 50 = 0.45 lM). Compound 4 was as potent as Gleevec (IC 50 = 0.56 lM) heralded as a 'magic bullet' against chronic myelogenous leukemia (CML). MAD analogues 7 and 8 containing an extended ethylenebis(phosphonate) linkage showed low nanomolar inhibition of IMPDH and low micromolar inhibition of K562 cells proliferation. Some novel MAD analogues described herein containing linkers of different length and geometry were found to inhibit IMPDH with K i 's lower than 100 nM. Thus, such linkers can be used for connection of other molecular fragments with high affinity to the N-and A-sub-site of IMPDH.
Journal of Biological Chemistry, 2007
The inosine monophosphate cyclohydrolase (IMPCH) component (residues 1-199) of the bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase, residues 200-593)/IMPCH (ATIC) catalyzes the final step in the de novo purine biosynthesis pathway that produces IMP. As a potential target for antineoplastic intervention, we designed IMPCH inhibitors, 1,5-dihydroimidazo[4,5-c][1,2,6]thiadiazin-4(3H)-one 2,2-dioxide (heterocycle, 1), the corresponding nucleoside (2), and the nucleoside monophosphate (nucleotide) (3), as mimics of the tetrahedral intermediate in the cyclization reaction. All compounds are competitive inhibitors against IMPCH (K i values ؍ 0.13-0.23 M) with the simple heterocycle 1 exhibiting the most potent inhibition (K i ؍ 0.13 M). Crystal structures of bifunctional ATIC in complex with nucleoside 2 and nucleotide 3 revealed IMPCH binding modes similar to that of the IMPCH feedback inhibitor, xanthosine 5-monophosphate. Surprisingly, the simpler heterocycle 1 had a completely different IMPCH binding mode and was relocated to the phosphate binding pocket that was identified from previous xanthosine 5-monophosphate structures. The aromatic imidazole ring interacts with a helix dipole, similar to the interaction with the phosphate moiety of 3. The crystal structures not only revealed the mechanism of inhibition of these compounds, but they now serve as a platform for future inhibitor improvements. Importantly, the nucleosidecomplexed structure supports the notion that inhibitors lacking a negatively charged phosphate can still inhibit IMPCH activity with comparable potency to phosphate-containing inhibitors. Provocatively, the nucleotide inhibitor 3 also binds to the AICAR Tfase domain of ATIC, which now provides a lead compound for the design of inhibitors that simultaneously target both active sites of this bifunctional enzyme.
Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Inosine 5 0 -monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with k on values of 0.7 Â 10 4 to 9.3 Â 10 4 M À1 Ás À1 . Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors.
Inosine Monophosphate Dehydrogenase (IMPDH) plays very important role in Guanosine Monophosphate (GMP) biosynthesis. Type I hIMPDH is expressed at lower levels in all cells, whereas type II is especially observed in acute myelogenous leukaemia, chronic myelogenous leukaemia cancer cells, so it is thought to be an active target for leukemic drug design. MD-simulation studies of the solvated modeled structure of hIMPDH (PDB Id: 1B3O) in presence of NAD + have revealed some interesting feature on the role of some conserved water molecules in the binding of IMP to enzyme. Based on H-bonding interaction of IMP with Asp 364, Arg 322, Asp 274, Cys 331 and Asn 303 residues in the X-ray and simulated structures, and the recognition dynamics of O 2 ' and O 3 ' ribose hydroxyl groups (of IMP) with the conserved water molecules, we have modified the hydroxyl group of IMP and modeled a few number of derivatives. Optimization of ligand structures, followed by docking in enzyme, solvation, energy minimization of the protein-ligand complexes and their successive all atoms simulation studies have been made up to 5 ns. After critical investigation of different snapshots, the stereochemical quality, binding affinity/energy of the modified ligand is calculated and have screened three IMP-analogs (modified at O 2 ' and O 3 ' ribose oxygen), which can also effectively interact with the residues of the mononucleotide binding pocket and may thought to act as inhibitor for IMPDH. The drug likeness and drug score of the modeled compounds are observed to be better.