Arzneimittelforschung 2011; 61(1): 66-72
DOI: 10.1055/s-0031-1296169
Special Themes
Editio Cantor Verlag Aulendorf (Germany)

Human dihydroorotate dehydrogenase inhibitors, a novel approach for the treatment of autoimmune and inflammatory diseases

Johann Leban
1   4SC AG, Martinsried, Germany
,
Daniel Vitt
1   4SC AG, Martinsried, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
28 November 2011 (online)

Abstract

Dihydroorotate dehydrogenase (DHODH), a novel and recently discovered enzyme, is involved in the biosynthesis of uridine. Leflunomide (CAS 75706-12-6), a drug approved for the treatment of treat rheumatoid arthritis (RA), was identified as an inhibitor of DHODH.

Structure based drug design using the leflunomide/DHODH X-ray structure yielded novel inhibitors with improved pharmacological properties. Such drug candidates are in clinical trials against various autoimmune diseases.

 
  • References

  • 1 Woods DD. The relation of p-aminobenzoic acid to the mechanism of the action of sulfanilamide. Br J Exp Path. 1940; 21: 74
  • 2 Fildes P. A rational approach to research in chemotherapy. Lancet. 1940; 235: 955-7
  • 3 Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA. Temporary remissions in acute leukaemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med. 1948; 238: 787-93
  • 4 Willkens RF, Watson MA. Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med. 1982; 100 (3) 314-21
  • 5 Steinsson K, Weinstein A, Korn J, Abeles M. Low dose methotrexate in rheumatoid arthritis. J Rheumatol. 1982; Nov–Dec 9 (6) 860-6
  • 6 Hitchings Jr GH. Selective inhibitors of dihydrofolate reductase. Les prix Nobel. 1988; 296-313
  • 7 Elion GB. The purine path of chemotherapy. Science. 1989; 24 (4900) 41-7
  • 8 Hedstorm L. IMP dehydrogenase: structure, mechanism and inhibition. Chem Rev. 2009; 109 (7) 2903-28
  • 9 Hong Z, Craig E. Pleiotropic mechanism of ribavirin antiviral activities. Prog Drug Res. 2002; 59: 41-69
  • 10 Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA. Importance of ribunucleotide availability to proliferating T lymphocytes from healthy humans. J Biol Chem. 1995; 270 (50) 29682-9
  • 11 Löffler M, Jöckel J, Schuster G, Becker C. Dihydroorotatubiquinone oxidoreductase links mitochondria in the bio-synthesis of pyrimidine nucleotides. Mol Cell Biochem. 1997; 174: 125-9
  • 12 Löffler M, Grein K, Knecht W, Klein A, Bergjohann U. Dihydroorotate Dehydrogenase. Purine Pyrimidine Metab Man. 1998; 507-14
  • 13 Douglas GB. Inhibitors of dihydroorotate dehydrogenase. Exp Opin Ther Pat. 1999; 9 (1) 41-54
  • 14 Cramer DV. Brequinar sodium. Transplant Proc. 1996; 28 (2) 960-3
  • 15 Joshi AS, King SY, Zajac BA, Makowka L, Sher LS, Kahan BD et al Phase I safety and pharmacokinetic studies of brequinar sodium after single ascending oral doses in stable renal, hepatic, and cardiac allograft recipients. J Clin Pharmacol. 1997; 37 (12) 1121-8
  • 16 Schiff MH, Strand V, Oed C, Loew-Friedrich I. Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis. Drugs Today. 2000; 36 (6) 383-94
  • 17 Li EK, Tam LS, Tomlinson B. Leflunomide in the treatment of rheumatoid arthritis. Clin Ther. 2004; 26 (4) 447-59
  • 18 Osiri M, Shea B, Robinson V, Suarez-Almazor M, Strand V, Tugwell P et al Leflunomide for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2003; 1: CD002047
  • 19 Prakash A, Jarvis B. Leflunomide: a review of its use in active rheumatic arthritis. Drugs. 1999; 58 (6) 1137-64
  • 20 Kaltwasser JP, Nash P, Gladman D, Rosen CF, Behrens F, Jones P et al Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis. Arthritis Rheum. 2004; 50: 1939-50
  • 21 Kiely PD. The broadening use of leflunomide in clinical practice. Hosp Med. 2004; 65 (12) 735-9
  • 22 Robertson SM, Lang LS. Leflunomide: inhibition of S-anti-gen induced autoimmuneuveitis in Lewis rats. Agents Action. 1994; 42: 167-72
  • 23 O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GPA, Confavraux C et al A phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses. Neurology. 2006; 66: 894-900
  • 24 Pinto P, Dougados M. Leflunomide in clinical practice. Acta Rheumatol Port. 2006; 31 (3) 215-24
  • 25 Boyd B Castaner. Teriflunomide: agent for multiple sclerosis. dihydroorotate dehydrogenase inhibitor. Drugs Future. 2005; 30 (11) 1102-6
  • 26 Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for rheumatoid arthris: fact or fiction?. Arthritis Rheum. 2005; 52: 2975-83
  • 27 Katchamart W, Trudeau J, Phumethum V, Bombardier C. The efficacy and toxicity of Methotrexate (MTX) monotherapy with non-biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: a systematic review and metaanalysis. Ann Rheum Dis. 2009; 68: 1105-12
  • 28 Bao C, Chen S, Gu Y, Lao Z, Ni L, Yu Q et al Leflunomide, a new disease-modifying drug for treating rheumatoid arthritis in methotrexate-controlled phase II clinical trial. Chin Med J. 2003; 116 (8) 1228-34
  • 29 Weinblatt EM, Dixon J, Falchuk KR. Serious liver disease in a patient receiving metotrexate and leflunomide. Arthritis Rheum. 2000; 43 (11) 2609-13
  • 30 Kirsch BM, Zeyda M, Stuhlmeier K, Grisar J, Smolen JS, Watschinger B et al The active metabolite of leflunomide, A77 1726, interferes with dentritic cell function. Arthritis Res Ther. 2005; 7 (3) R694-703
  • 31 Siemasko K, Chong ASF, Jäck HM, Gong H, Williams JW, Finnegan A. Inhibition of JAK3 and STAT6 tyrosine sphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol. 1998; Feb 15 160 (4) 1581-8
  • 32 Gonzalez-Alvaro I, Garcia AMO, Dominguez-Jiminez C et al Inhibition of TNF and IL-17 production by leflunomide involves the JAK/STAT pathway. Ann Rheum Dis. 2009; 68: 144-1650
  • 33 Ullrich A, Knecht W, Fries M, Loffler M. Recombinant expression of N-terminal truncated mutants of the membrane bound mouse, rat and human flavoenzyme dihydroorotate dehydrogenase: a versatile tool to rate inhibitor effects?. J Bio Chem. 2001; 268 (6) 1861-8
  • 34 Liu S, Neidhardt EA, Trudy HG, Ocain T, Clardy J. Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents. Structure. 2000; 8 (1) 25-33
  • 35 Sutton AE, Clardy J. The synthesis of potentially selective inhibitors of dihydroorotate dehydrogenase. The utilization of chemoselective Suzuki cross-coupling reactions in a parallel synthesis. Tetrahedron Lett. 2001; 42: 547
  • 36 Pospisil P, Kuon T, Scapozza L, Folkers GJ. Methodology and problems of protein-ligand docking: case study of dihydroorotate dehydrogenase, thymidine kinase, and phosphodiesterase 4. J Recept Signal Transduction. 2002; 22 (1) 141-154
  • 37 Herz T, Wolf K, Kraus J, Kramer B. 4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds. Exp Opin Drug Metab Toxicol. 2006; 2 (3) 471-83
  • 38 Wolf K. High-throughput docking, a case study. International workshop on new approaches in drug design and discovery. Schloss Rauischholzhausen, Germany;. 2003;
  • 39 Ortez D, Munoz-Colado C, Garcia-Domenech R, Gimeno-Cardona C. Virtual combinatorial syntheses and computational screening of new potentional anti-herpes compounds. J Med Chem. 1999; 42: 3308-14
  • 40 Leban J, Saeb W, Garcia G, Baumgartner R, Kramer B. Discovery of a novel series of DHODH inhibitors by a docking procedure and QSAR refinement. Bioorg Med Chem Lett. 2004; 14: 55-8
  • 41 Leban J, Kralik M, Mies J, Baumgartner R, Gassen M, Tasler S. Biphenyl-4-ylcarbamoyl thiophene carboxylic acids as potent DHODH inhibitors. Bioorg Med Chem Lett. 2006; 15: 267-70
  • 42 Leban J, Kralik M, Mies J, Gassen M, Tentschert K, Baumgartner R. SAR, species specificity, and cellular activity of cyclopentene dicarboxylic acid amides as DHODH inhibitor. Bioorg Med Chem Lett. 2005; 4854-7
  • 43 Baumgartner R, Walloschek M, Kralik M, Gotschlich A, Tasler S, Mies J et al Dual binding mode of a novel series of DHODH inhibitors. J Med Chem. 2006; 49: 1239-47
  • 44 Walse B, Tamu Tufe V, Svennson B, Fritzson I, Dahlberg L, Khairoullina A et al The structure of human dihydroorotate dehydrogenase with and without inhibitor reveal conformational flexibility in the inhibitor and substrate binding sites. Biochemistry. 2008; 47: 8929-36
  • 45 Fritzson I, Svensson B, Al-Karadaghi S, Walse B, Wellmar U, Nilsson UJ et al Inhibition of human DHODH by 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids identified by structure-guided fragment selection. Chem Med Chem. 2010; 5: 608-17
  • 46 Castro Palomino Laria JC, Erra Sola M, Lozoya Toribio ME, Navarro Romero E. Amino nicotinic and isonicotinic acid derivates as DHODH inhibitors. WO 2008/077639 (A1): WO 2007EP11401 20071221.
  • 47 Strobl S, Leban J, Baumgartner R, Ammendola A. DHODH Inhibitors – from virtual screening to clinical phase II. Symposium on nucleosides and nucleotides, Stockholm, Sweden;. 2009;
  • 48 Press release 4SC AG 28 May, 2009 ( www.4sc.com ).
  • 49 Fitzpatrick LR, Deml L, Hofman L, Small JS, Groeppel M, Hamm S et al A novel immunosuppressive drug (4SC-101) improves TNBS-induced colitis in mice. Inflamm Bowel Dis. 2010; Oct 16 (10) 1763-77
  • 50 Kulkarni OP, Sayyyed SG, Kantner C, Ryu M, Schnurr M, Sardy M et al 4SC-101, a novel small molecule dihydroorotate dehydrogenase inhibitor, suppresses systemic lupus erythematosus in MRL-(Fas)lpr mice. Am J Pathol. 2010; 176 (6) 2840-7