SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors

Leban, Johann; Kralik, Martin; Mies, Jan; Gassen, Michael; Tentschert, Karin; Baumgartner, Roland

doi:10.1016/j.bmcl.2005.07.053

Cited by 35 publications

(30 citation statements)

References 5 publications

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“…7,8 SC12267 (designated 4SC-101) is a novel immunosuppressive drug inhibiting DHODH. 9,10 The chemical structure of 4SC-101 ( Fig. 1) is considerably different from teriflunomide.…”

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confidence: 99%

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

Fitzpatrick

Deml

Hofmann

et al. 2010

Inflammatory Bowel Diseases

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“…7,8 SC12267 (designated 4SC-101) is a novel immunosuppressive drug inhibiting DHODH. 9,10 The chemical structure of 4SC-101 ( Fig. 1) is considerably different from teriflunomide.…”

mentioning

confidence: 99%

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

Fitzpatrick

Deml

Hofmann

et al. 2010

Inflammatory Bowel Diseases

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“…13 The chemical structure of 4SC-101 ( Figure 1) is considerably different from the active metabolite of leflunomide. 4SC-101 inhibits human DHODH with a half maximal inhibitory concentration (IC 50 ) value of 134 nmol/L, and the proliferation of phytohemagglutinin-stimulated lymphocytes with an IC 50 value of about 13 mol/L.…”

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confidence: 99%

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Kulkarni

Sayyed

Kantner

et al. 2010

The American Journal of Pathology

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Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/ week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal , dermal , and pulmonary SLE manifestations of MRL(Fas)lpr mice. However , even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts , which were significantly reduced in CYC-treated mice. Together , the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence , DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC. (Am J Pathol

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“…A data set of 34 compounds (hDHODH inhibitors) was collected from the literatures [21,22]. The experimental IC 50 values (50% inhibitory concentration of the enzyme) were evaluated by Leban et al [21,22] in an enzyme assay using N-terminally truncated recombinant hDHODH.…”

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CoMFA and CoMSIA Studies on Aryl Carboxylic Acid Amide Derivatives as Dihydroorotate Dehydrogenase (DHODH) Inhibitors

Vyas

Ghate²

2012

CAD

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DHODH is a flavoenzyme that catalyzes the oxidation of dihydroorotate (DHO) to orotate (ORO) as part of the fourth and rate limiting step of the de novo pyrimidine biosynthetic pathway. Inhibitors of DHODHs have proven efficacy for the treatment of cancer, malaria and immunological disorders. 3D QSAR studies on some aryl carboxylic acid amide derivatives as hDHODH inhibitors were performed by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices (CoMSIA) methods to rationalize the structural requirements responsible for the inhibitory activity of these compounds. The alignment strategy was used for these compounds by means of Distill function defined in SYBYL X 1.2. The best CoMFA and CoMSIA models obtained for the training set were statistically significant with cross-validated coefficients (q²) of 0.636 and 0.604 and conventional coefficients (r²) of 0.993 and 0.950, respectively. Both the models were validated by an external test set of five compounds giving satisfactory prediction (r² pred) of 0.563 and 0.523 for CoMFA and CoMSIA models, respectively. Further the robustness of the model was verified by bootstrapping analysis. Generated CoMFA and CoMSIA models provide useful information for the design of novel inhibitors with good hDHODH inhibitory.

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SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitors

Cited by 35 publications

References 5 publications

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

CoMFA and CoMSIA Studies on Aryl Carboxylic Acid Amide Derivatives as Dihydroorotate Dehydrogenase (DHODH) Inhibitors

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