Low molecular weight indole fragments as IMPDH inhibitors

Beevers, Rebekah E.; Buckley, George M.; Davies, Natasha; Fraser, Joanne L.; Galvin, Francis C.; Hannah, Duncan R.; Haughan, Alan F.; Jenkins, Kerry; Mack, Stephen R.; Pitt, William R.; Ratcliffe, Andrew J.; Richard, Marianna D.; Sabin, Verity; Sharpe, Andrew; Williams, Sophie C.

doi:10.1016/j.bmcl.2006.01.089

Cited by 19 publications

(9 citation statements)

References 15 publications

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“…Recently, a variety of compounds with structures different from MPA and BMS-566419 were reported to inhibit IMPDH activity [19,20,[36][37][38][39]. In addition, several studies reported that a number of these compounds potentially prevent graft rejection in mice transplant models [19,20].…”

Section: Discussionmentioning

confidence: 97%

Effect of the inosine 5′-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection

Nakanishi

Morokata

Kubo

et al. 2010

International Immunopharmacology

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Section: Discussionmentioning

confidence: 97%

Effect of the inosine 5′-monophosphate dehydrogenase inhibitor BMS-566419 on rat cardiac allograft rejection

Nakanishi

Morokata

Kubo

et al. 2010

International Immunopharmacology

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“…Thus, quantitative pharmacophore modelling was carried out. Twenty‐five IMPDH inhibitors (19–37) with sufficient diversity in bioactivity and structure were selected to form a training set to generate a pharmacophore model based on their activity values (IC 50 ). Their IC 50 ranged from 4 n m to 32 μ m .…”

Section: Methodsmentioning

confidence: 99%

“…A good pharmacophore is not only able to predict the activity of the training set compounds correctly, but also capable of predicting the activity of external compounds to the training set. To validate the pharmacophore model obtained, we selected 75 IMPDH inhibitors [26–100 (19–37)] as the test set for the pharmacophore model. The structures and activities are shown in Scheme S1 and Tables S1, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…There has been significant success in the discovery of IMPDH‐targeted drugs thus far (10–37). Several compounds such as amides (19), oxazolyl indoles (20), phenyl‐amino oxazoles (21), guanidines (23), triazines (24), isoquinoline aminooxazoles (26), quinolones (28,31), quinazolinones (33), quinazolinethiones and quinazolinediones (34), indoles (35,36), acridones (37) have been reported to inhibit IMPDH activity at low micromolar concentrations. The increasing knowledge base of the IMPDH structure, activity and regulation lays foundation for summarizing essential chemical feature, which may inspire the development of novel IMPDH inhibitors.…”

mentioning

confidence: 99%

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A Three‐Dimensional Pharmacophore Model for IMPDH Inhibitors

Yang

Wang

et al. 2011

Chem Biol Drug Des

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Inosine 5'-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial and anticancer therapeutic areas. In this study, a chemical feature-based pharmacophore model of IMPDH inhibitors has been firstly developed with the aid of the HypoRefine protocol within Discovery Studio 2.5. The best model for IMPDH inhibitors, Hypo1-1, was characterized by the best correlation coefficient (0.97595) and the lowest RMSD (0.582058). It consisted of one hydrogen-bond donor, one hydrogen-bond acceptor, one aromatic ring and one hydrophobic feature, as well as two excluded volumes. The model was validated using a wide range of test molecules and a cross-validation. Furthermore, the pharmacophore features were confirmed by molecular docking studies. The pharmacophore model could quantitatively predict inhibitor activity and identify highly potent molecules. Therefore, the present results could be valuable for the discovery and development of specific IMPDH inhibitors.

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“…Recently, a variety of compounds with structures different from MPA or MMF have been reported to inhibit IMPDH activity [20][21][22][23]. In addition, several studies have reported that a number of these compounds potentially prevent acute rejection in mice transplant models [24,25].…”

Section: Contents Lists Available At Sciencedirectmentioning

confidence: 98%