Immunosuppressive structure-activity relationships of Brequinar and related cinchoninic acid derivatives

Batt, Douglas G.; Copeland, Robert A.; Dowling, Randine L.; Gardner, Tracy L.; Jones, Elizabeth A.; Orwat, Michael J.; Pinto, Donald; Pitts, William J.; Magolda, Ronald L.; Jaffee, Bruce

doi:10.1016/0960-894x(95)00252-o

Cited by 27 publications

(20 citation statements)

References 4 publications

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“…Since it has been reported that the -COOH group at the R 4 position is favorable for DHODH activity (Batt et al, 1995;Batt et al, 1998; Munier-Lehmann, Vidalain, Tangy, & Janin, 2013), we proceeded to synthesize seven benzimidazole carboxylic acid derivatives ( Table 1). All these compounds have a methyl group at R 2 position, along with varied substitutions primarily on the second phenyl ring.…”

Section: Structure-activity Relationship (Sar) Studiesmentioning

confidence: 99%

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

Abdullah

Chee

Lee

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Structure-activity Relationship (Sar) Studiesmentioning

confidence: 99%

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

Abdullah

Chee

Lee

et al. 2015

Bioorganic & Medicinal Chemistry

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“…12 Pyrimidines are essential for the biosynthesis of DNA, RNA, and phospholipids. 13 Inhibition of DHODH causes reduced levels of pyrimidine nucleotides that in turn trigger various activities such as, anticancer, 14 immunosuppressive, 15 antimalarial, 16 and antifungal. 17 Additionally, inhibition of DHODH can be beneficial for spinal cord injury and rheumatoid arthritis.…”

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confidence: 99%

“…17 Additionally, inhibition of DHODH can be beneficial for spinal cord injury and rheumatoid arthritis. 18 Various DHODH inhibitors have evolved over the years out of which brequinar 15 and leflunomide 18 have gained a lot of attention due to their high potency. Recently, we described the discovery of 4-quinoline carboxylic acids with anti viral (IC 50 = 110 nM for VSV) activity via a high-throughput screen and brief SAR study, 19 and disclosed the target enzyme for the anti viral activity to be human DHODH.…”

mentioning

confidence: 99%

“…15,22-24 For example, a free carboxylic acid is crucial, whereas a hydrophobic moiety is necessary at C(2). Additionally, electron withdrawing groups such as fluorine, chlorine and trifluoromethyl have a beneficial effect at C(7).…”

mentioning

confidence: 99%

“…Lastly, it was reported that although the methyl group at C(3) of brequinar did not influence DHODH activity, it did significantly improve cellular activity in a mixed lymphocyte reaction (MLR) assay. 15 …”

mentioning

confidence: 99%

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SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

Das

Deng

Zhang

et al. 2013

ACS Med. Chem. Lett.

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It is established that drugs targeting viral proteins are at risk of generating resistant strains. However, drugs targeting host factors can potentially avoid this problem. Herein we report structure-activity relationship studies leading to the discovery of a very potent lead compound 6-fluoro-2-(5-isopropyl-2-methyl-4-phenoxyphenyl)quinoline-4-carboxylic acid (C44) that inhibits human dihydroorotate dehydrogenase (DHODH) with an IC50 of 1 nM, and viral replication of VSV and WSN-Influenza with an EC50 of 2 nM and 41 nM. We also solved the X-ray structure of human DHODH bound to C44, providing structural insight into the potent inhibition of biaryl ether analogs of brequinar.

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Organ TransplantDrugs

Kundu

2003

Burger's Medicinal Chemistry and Drug Discovery

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In recent years several new immunosuppressive agents for organ transplantation have been introduced for clinical usage. They have greater efficacy and fewer side effects than those of the classical therapies involving corticosteroids, azathioprine, and cyclosporine. The new maintenance immunosuppressive drugs are either immunophilin‐binding drugs or are inhibitors of de novo synthesis of nucleotides (purines or pyrimidines) that inhibit signal transduction in lymphocytes. The immunophilin‐binding drugs are cyclosporine, tacrolimus, and rapamycin, whereas inhibitors of de novo nucleotide synthesis include mycophenolate mofetil, mizoribine, brequinar, and leflunomide. Gusperimus (deoxyspergualin), which inhibits IL‐1 synthesis, was useful in reversing early and late acute rejection in clinical trials. FTY‐720, another promising drug, prolonged the survival of allografts and synergized with cyclosporin and sirolimus in experimental models. Antibody preparations such as OKT3, as well as the newer recombinant products, which specifically bind to the IL‐2 receptor, basiliximab, and daclizumab, not only reduced acute rejection but were associated with few adverse effects. Antisense oligonucleotides that interfere with the intercellular adhesion molecules involved in rejection gave encouraging results in primate renal allografts. Use of stem cells, donor bone marrow, and xenotransplantation are some of the alternatives that are likely to find application in organ transplantation in the near future.

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Immunosuppressive structure-activity relationships of Brequinar and related cinchoninic acid derivatives

Cited by 27 publications

References 4 publications

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH

SAR-Based Optimization of a 4-Quinoline Carboxylic Acid Analogue with Potent Antiviral Activity

Organ TransplantDrugs

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