Publikationsserver der Universitätsbibliothek Marburg
Titel:Design und Synthese neuartiger Grundstrukturen zur Inhibition von Aspartat-Proteasen der Familien A1 und A2
Autor:Linde, Kerstin
Weitere Beteiligte: Diederich, Wibke E. (Prof. Dr.)
Veröffentlicht:2012
URI:https://archiv.ub.uni-marburg.de/diss/z2012/0082
DOI: https://doi.org/10.17192/z2012.0082
URN: urn:nbn:de:hebis:04-z2012-00822
DDC: Naturwissenschaften
Titel (trans.):Design and Synthesis of new Scaffolds for the Inhibition of Aspartic Proteases of the A1 and A2 families
Publikationsdatum:2012-03-19
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
hydroxylamines, Mitsunobu-Staudinger-Reaktion, inhibitor-design, Mitsunobu-Staudinger-reaction, Hydroxylamine, Aspartat-Protease, Inhibitordesign, piperidine, aspartic-protease, Piperidine
Referenziert von:

Zusammenfassung:
Nach der Endeckung des HI-Virus als Auslöser von AIDS sind mehr als 20 verschiedene Präparate gegen diese Erkrankung in die klinische Praxis eingeführt worden. Damit sind gegen AIDS mehr Virostatika erhältlich als gegen alle anderen Viruserkrankungen gemeinsam. 1995 wurde der erste HIV Protease Inhibitor in der HAART (engl. Highly Active Antiretroviral Therapy) eingesetzt, und es gelang, sowohl die Lebensqualität als auch die Lebenserwartung der Patienten unter dieser Therapie deutlich zu erhöhen. Trotz des großen Erfolges von HAART ist es unverzichtbar, dass sowohl akademische Institutionen als auch die pharmazeutische Industrie die Bemühungen fortsetzen, um potentere und insbesondere im Hinblick auf den Bindungsmodus andersartige Wirkstoffe zu entwickeln. Zum einen stellt die Resistenzbildung gegen die aktuell verfügbaren Medikamente ein gravierendes Problem dar. Zum anderen erfordern die schlechten Bioverfügbarkeiten und hohen Toxizitäten der zugelassenen Wirkstoffe weitere Verbesserungen und machen die Forschung auf diesem Gebiet weiterhin unabdingbar. Auch unter den Mitgliedern der Familie A1 gibt es vielversprechende Zielenzyme, deren Bedarf nach neuartigen Leitstrukturen noch nicht gedeckt ist. Das einzige zugelassene Medikament für die Inhibition des Enzyms Renin ist Aliskiren, für Cathepsin D und für BACE1 hat es trotz intensiver Forschungsbemühungen noch kein Wirkstoff bis zur Markteinführung geschafft. In der vorliegenden Arbeit wurden neuartige Substanzklassen für die Inhibition der Aspartat-Proteasefamilien A1 und A2 identifiziert. Als Modellenzyme wurden Endothiapepsin als ein Vertreter der Familie A1 und die HIV-Protease als Vertreter der Familie A2 ausgewählt. Mit zyklischen Harnstoffen, Piperidin-Diestern, dreiarmigen Piperidinen, offenkettigen primären Aminen und Hydroxylaminen wurden fünf unterschiedliche Inhibitorklassen Computer-basiert entwickelt, synthetisiert und bezüglich ihrer Affinität gegen Endothiapepsin und die HIV-Protease analysiert. Dabei ist es gelungen, für jede Substanzklasse, mit Ausnahme der zyklischen Harnstoffe, mindestens einen Inhibitor bis in den submikromolaren Affinitätsbereich hinein zu optimieren. Die Inhibitorklasse der zyklischen Harnstoffe konnte gegen Endothiapepsin bis in den niedrigen mikromolaren Bereich verbessert werden, was in Anbetracht der geringen Größe der Verbindung und der Dekoration mit nur zwei Substituenten ein sehr gutes Ergebnis darstellt. Mit den Piperidin-Diestern konnte ebenfalls ein vielversprechendes Grundgerüst zur Hemmung von Aspartat-Proteasen der Familie A1 entwickelt werden. Zwei Verbindungen dieser Serie zeigen Affinitäten gegen Endothiapepsin von 750 nM, obwohl auch hier nur zwei Substituenten für die Besetzung der Spezifitätstaschen zur Verfügung stehen. Die Affinitäten dieser Verbindungsklasse können sicherlich durch gezielte Optimierung weiter erhöht werden. In der Substanzklasse der dreiarmigen Piperidine konnte keine weitere Verbesserung erreicht werden. In der Serie von elf synthetisierten Inhibitoren lagen dabei neun mindestens im einstellig mikromolaren Aktivitätsbereich. Auch für die HIV-Protease konnte in dieser Serie die Affinität für das Indazol-Derivat auf 14 M verbessert werden. In der Substanzklasse der offenkettigen, primären Amine konnte eine Verbindung mit 500 nM gegenüber Endothiapepsin ein potenter Inhibitor dargestellt werden. Auch die anderen Inhibitoren dieser Serie zeigen moderate bis gute Affinitäten gegen dieses Enzym, wohingegen die Affinitäten gegen die HIV-Protease deutlich schlechter sind und im zweistellig mikromolaren Bereich liegen. In den bisher vorgestellten vier Verbindungsklassen waren die Inhibitionswerte gegen Endothiapepsin denen der HIV-Protease deutlich überlegen. Umgekehrt ist dies bei der Inhibitorklasse der Hydroxylamine. Durch Variation des Substitutionsmusters konnten innerhalb dieser Substanzklasse zwei Verbindungen gegen die HIV-Protease nanomolare Aktivitäten erreichen. Das Triflourmethyl-Derivat zeigt einen Ki von 140 nM, was für eine initiale Serie ohne Kenntnisse über den Bindungsmodus ein ausgesprochen gutes Ergebnis darstellt. Bei den Hydroxylamin-Derivaten konnte innerhalb der Serie eine klare Struktur-Wirkungsbeziehung aufgestellt werden, durch die fundierte Annahmen über den Bindungsmodus möglich sind. Somit stellen die Hydroxylamine die vielversprechendste Substanzklasse dieser Arbeit für die Weiterentwicklung eines hoch potenten Inhibitors gegen die HIV-Protease dar. Während dieser Arbeit wurde eine Eintopf-Methode zur Darstellung von Aminen aus Alkoholen entwickelt sowie eingehende Untersuchungen mit dem Detergenz Triton X-100 und dessen Einfluss auf die Assay Ergebnisse durchgeführt.

Bibliographie / References

  1. Wlodawer, A., M. Miller, M. Jaskolski, B.K. Sathyanarayana, E. Baldwin, I.T. Weber, L.M. Selk, L. Clawson, J. Schneider, and S.B. Kent, Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science, 1989. 245(4918): p. 616-621.
  2. Daenke, S., H.J. Schramm, and C.R.M. Bangham, Analysis of substrate cleavage by recombinant protease of human T cell leukaemia virus type 1 reveals preferences and specificity of binding. Journal of General Virology, 1994. 75: p. 2233-2239.
  3. Kopple, Molecular Properties That Influence the Oral Bioavailability of Drug Candidates. Journal of Medicinal Chemistry, 2002. 45(12): p. 2615- 2623. 253
  4. Foundling, S.I., J. Cooper, F.E. Watson, A. Cleasby, L.H. Pearl, B.L. Sibanda, A. Hemmings, S.P. Wood, T.L. Blundell, M.J. Valler, C.G. Norey, J. Kay, J. Boger, B.M. Dunn, B.J. Leckie, D.M. Jone, B. Atrash, A. Hallett, and M. Szelke, High resolution X-ray analyses of renin inhibitor-aspartic proteinase complexes. Nature, 1987. 327(6120): p. 349-352.
  5. Czodrowski, P., C.A. Sotriffer, and G. Klebe, Atypical Protonation States in the Active Site of HIV-1 Protease: A Computational Study. Journal of Chemical Information and Modeling, 2007. 47(4): p. 1590-1598.
  6. Böttcher, J., A. Blum, A. Heine, W.E. Diederich, and G. Klebe, Structural and Kinetic Analysis of Pyrrolidine-Based Inhibitors of the Drug-Resistant Ile84Val Mutant of HIV-1 Protease. Journal of Molecular Biology, 2008. 383(2): p. 347-357.
  7. McCabe, J.L. Duke, and C.-H. Chang, Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors. Journal of Biological Chemistry, 1998. 273(20): p. 12325-12331.
  8. Rawlings, N.D. and A.J. Barrett, MEROPS: the peptidase database. Nucleic Acids Research, 2000. 28(1): p. 323-325.
  9. Hudgson, D., Humphreys, Philip, Hughes, Steven, Widening the usefulness of epoxides and aziridines in synthesis. Pure and Applied Chemistry, 2007. 79(2): p. 269-279.
  10. Hamilton, D.J. and A. Sutherland, A flexible approach for the synthesis of selectively labelled l-arginine. Tetrahedron Letters, 2004. 45(29): p. 5739- 5741.
  11. Cooper, J.B., Aspartic Proteinases in Disease: A Structural Perspective. Current Drug Targets, 2002. 3(2): p. 155-173.
  12. Leung, D., G. Abbenante, and D.P. Fairlie, Protease Inhibitors: Current Status and Future Prospects. Journal of Medicinal Chemistry, 2000. 43(3): p. 305-341.
  13. Lombardi, V.C., F.W. Ruscetti, J. Das Gupta, M.A. Pfost, K.S. Hagen, D.L. Peterson, S.K. Ruscetti, R.K. Bagni, C. Petrow-Sadowski, B. Gold, M. Dean, R.H. Silverman, and J.A. Mikovits, Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science, 2009. 326(5952): p. 585-589.
  14. Pickering, L., B.S. Malhi, P.L. Coe, and R.T. Walker, 4'- Methyloxycarbamyl-3'-deoxy-5-methyluridine; synthesis of a novel nucleoside analogue. Tetrahedron, 1995. 51(9): p. 2719-2728.
  15. McGovern, S.L., E. Caselli, N. Grigorieff, and B.K. Shoichet, A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High- Throughput Screening. Journal of Medicinal Chemistry, 2002. 45(8): p. 1712-1722.
  16. Bose, A.K., J.F. Kistner, and L. Farber, A Convenient Synthesis of Axial Amines. The Journal of Organic Chemistry, 1962. 27(8): p. 2925-2927. 112.
  17. Cole, D.C., E.S. Manas, J.R. Stock, J.S. Condon, L.D. Jennings, A. Aulabaugh, R. Chopra, R. Cowling, J.W. Ellingboe, K.Y. Fan, B.L. Harrison, Y. Hu, S. Jacobsen, G. Jin, L. Lin, F.E. Lovering, M.S. Malamas, M.L. Stahl, J. Strand, M.N. Sukhdeo, K. Svenson, M.J. Turner, E. Wagner, J. Wu, P. Zhou, and J. Bard, Acylguanidines as Small-Molecule β-Secretase Inhibitors. Journal of Medicinal Chemistry, 2006. 49(21): p. 6158-6161. 63. Brass, S., N.-S. Chan, C. Gerlach, T. Luksch, J. Böttcher, and W.E. Diederich, Synthesis of 2,3,4,7-tetrahydro-1H-azepines as privileged ligand scaffolds for the design of aspartic protease inhibitors via a ring-closing metathesis approach. Journal of Organometallic Chemistry, 2006. 691(24- 25): p. 5406-5422.
  18. Secrist, J.A. and M.W. Logue, Amine hydrochlorides by reduction in the presence of chloroform. The Journal of Organic Chemistry, 1972. 37(2): p. 335-336.
  19. Yang, W., W. Lu, Y. Lu, M. Zhong, J. Sun, A.E. Thomas, J.M. Wilkinson, R.V. Fucini, M. Lam, M. Randal, X.-P. Shi, J.W. Jacobs, R.S. McDowell, E.M. Gordon, and M.D. Ballinger, Aminoethylenes: A Tetrahedral Intermediate Isostere Yielding Potent Inhibitors of the Aspartyl Protease BACE-1. Journal of Medicinal Chemistry, 2006. 49(3): p. 839-842.
  20. Monini, P., C. Sgadari, E. Toschi, G. Barillari, and B. Ensoli, Antitumour effects of antiretroviral therapy. Nat Rev Cancer, 2004. 4(11): p. 861-875.
  21. Edwards, P.D., J.S. Albert, M. Sylvester, D. Aharony, D. Andisik, O. Callaghan, J.B. Campbell, R.A. Carr, G. Chessari, M. Congreve, M. Frederickson, R.H.A. Folmer, S. Geschwindner, G. Koether, K. Kolmodin, J. Krumrine, R.C. Mauger, C.W. Murray, L.-L. Olsson, S. Patel, N. Spear, and G. Tian, Application of Fragment-Based Lead Generation to the Discovery of Novel, Cyclic Amidine β-Secretase Inhibitors with Nanomolar Potency, Cellular Activity, and High Ligand Efficiency. Journal of Medicinal Chemistry, 2007. 50(24): p. 5912-5925.
  22. Toth, M.V. and G.R. Marshall, A simple, continuous fluorometric assay for HIV protease. International Journal of Peptide and Protein Research, 1990. 36(6): p. 544-550.
  23. Fabiano, E., B.T. Golding, and M.M. Sadeghi, A Simple Conversion of Alcohols into Amines. Synthesis, 1987. 1987(02): p. 190,192.
  24. Ghosh, A.K., Aspartic Acid Proteases as Therapeutic Targets, ed. R. Mannhold, Kubinyi, H., Folkers, G. Vol. 45. 2010: WILEY-VCH. 23-25.
  25. Dash, C., A. Kulkarni, B. Dunn, and M. Rao, Aspartic Peptidase Inhibitors: Implications in Drug Development. Critical Reviews in Biochemistry and Molecular Biology, 2003. 38(2): p. 89-119.
  26. McGovern, S.L., B.T. Helfand, B. Feng, and B.K. Shoichet, A Specific Mechanism of Nonspecific Inhibition. Journal of Medicinal Chemistry, 2003. 46(20): p. 4265-4272.
  27. Pearl, L.H. and W.R. Taylor, A structural model for the retroviral proteases. Nature, 1987. 329(6137): p. 351-354.
  28. Nagel, U., Asymmetric Hydrogenation of α-(Acetylamino)cinnamic Acid with a Novel Rhodium Complex; the Design of an Optimal Ligand.
  29. Pineschi, M., Asymmetric Ring-Opening of Epoxides and Aziridines with Carbon Nucleophiles. European Journal of Organic Chemistry, 2006. 2006(22): p. 4979-4988.
  30. Jalaie, and J.J. Edmunds, Benzyl ether structure-activity relationships in a series of ketopiperazine-based renin inhibitors. Bioorganic & Medicinal Chemistry Letters, 2005. 15(21): p. 4713-4716.
  31. Kurtz, P., H. Schwarz, and H. Disselnkötter, Über 1-Cyan-alkene-(2) IV. Mitteilung über die Bildung von Nitrilen. Justus Liebigs Annalen der Chemie, 1960. 631(1): p. 21-56.
  32. Hoth, W. and G. Pyl, Über die Darstellung der Stickstoffwasserstoffsäure und ihrer Salze. Angewandte Chemie, 1929. 42(36): p. 888-891.
  33. Benes, P., V. Vetvicka, and M. Fusek, Cathepsin D--Many functions of one aspartic protease. Critical Reviews in Oncology/Hematology, 2008. 68(1): p. 12-28.
  34. Lowe, G., Chiral peptide nucleic acids with a n-aminoethyl-d-proline backbone U.S.P. Application, Editor. 2003.
  35. Corminboeuf, O., O. Bezencon, C. Grisostomi, L.u. Remen, S. Richard- Bildstein, D. Bur, L. Prade, P. Hess, P. Strickner, W. Fischli, B. Steiner, and A. Treiber, Design and optimization of new piperidines as renin inhibitors. Bioorganic & Medicinal Chemistry Letters, 2010. 20(21): p. 6286-6290. 142. Böttcher, J., A. Blum, S. Dörr, A. Heine, W.E. Diederich, and G. Klebe, Targeting the Open-Flap Conformation of HIV-1 Protease with Pyrrolidine- Based Inhibitors. ChemMedChem, 2008. 3(9): p. 1337-1344.
  36. Nguyen, J.-T., Y. Hamada, T. Kimura, and Y. Kiso, Design of Potent Aspartic Protease Inhibitors to Treat Various Diseases. Archiv der Pharmazie, 2008. 341(9): p. 523-535.
  37. Institut für Pharmazeutische Chemie, Philipps- Universität Marburg Promotionsarbeit: " Design und Synthese neuartiger Grundstrukturen zur Inhibition von Aspartat-Proteasen der Familien A1 und A2 " , betreut von Frau Prof. Dr. Wibke E. Diederich 02. 2007 – 08. 2007
  38. Adams, L.A., V.K. Aggarwal, R.V. Bonnert, B. Bressel, R.J. Cox, J. Shepherd, J. de Vicente, M. Walter, W.G. Whittingham, and C.L. Winn, Diastereoselective Synthesis of Cyclopropane Amino Acids Using Diazo 7 LITERATURVERZEICHNIS Compounds Generated in Situ. The Journal of Organic Chemistry, 2003. 68(24): p. 9433-9440.
  39. Lal, B., B.N. Pramanik, M.S. Manhas, and A.K. Bose, Diphenylphosphoryl azide a novel reagent for the stereospecific synthesis of azides from alcohols. Tetrahedron Letters, 1977. 18(23): p. 1977-1980.
  40. Veerapandian, B., J.B. Cooper, A. Šali, T.L. Blundell, R.L. Rosati, B.W. Dominy, D.B. Damon, and D.J. Hoover, Direct observation by X-ray analysis of the tetrahedral " intermediate " of aspartic proteinases. Protein Science, 1992. 1(3): p. 322-328.
  41. Webb, R.L., N. Schiering, R. Sedrani, and J.r. Maibaum, Direct Renin Inhibitors as a New Therapy for Hypertension. Journal of Medicinal Chemistry, 2010. 53(21): p. 7490-7520.
  42. Holsworth, D.D., M. Jalaie, T. Belliotti, C. Cai, W. Collard, S. Ferreira, N.A. Powell, M. Stier, E. Zhang, P. McConnell, I. Mochalkin, M.J. Ryan, J. Bryant, T. Li, A. Kasani, R. Subedi, S.N. Maiti, and J.J. Edmunds, Discovery of 6-ethyl-2,4-diaminopyrimidine-based small molecule renin inhibitors. Bioorganic & Medicinal Chemistry Letters, 2007. 17(13): p. 3575-3580.
  43. Geschwindner, S., L.-L. Olsson, J.S. Albert, J. Deinum, P.D. Edwards, T. de Beer, and R.H.A. Folmer, Discovery of a Novel Warhead against β- Secretase through Fragment-Based Lead Generation. Journal of Medicinal Chemistry, 2007. 50(24): p. 5903-5911.
  44. Coyne, A.G., D.E. Scott, and C. Abell, Drugging challenging targets using fragment-based approaches. Current Opinion in Chemical Biology, 2010. 14(3): p. 299-307.
  45. Williams, D.B.G. and M. Lawton, Drying of Organic Solvents: Quantitative Evaluation of the Efficiency of Several Desiccants. The Journal of Organic Chemistry, 2010. 75(24): p. 8351-8354.
  46. Ryan, A.J., N.M. Gray, P.N. Lowe, and C.-w. Chung, Effect of Detergent on "Promiscuous" Inhibitors. Journal of Medicinal Chemistry, 2003. 46(16): p. 3448-3451.
  47. Ezgimen, M.D., N.H. Mueller, T. Teramoto, and R. Padmanabhan, Effects of detergents on the West Nile virus protease activity. Bioorganic & Medicinal Chemistry, 2009. 17(9): p. 3278-3282.
  48. Katritzky, A.R., B. Pilarski, and L. Urogdi, Efficient Conversion of Nitriles to Amides with Basic Hydrogen Peroxide in Dimethyl Sulfoxide. Synthesis, 1989. 1989(12): p. 949,950. 99. Miyashita, M., A. Yoshikoshi, and P.A. Grieco, Pyridinium p 257
  49. Protease Inhibitor: Elucidation of the Binding Mode and Its Application in the Design of Related Analogs. Journal of Medicinal Chemistry, 1994. 37(17): p. 2664-2677.
  50. Roudeau, R., D. Gomez Pardo, and J. Cossy, Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)- dihydroxypiperidine derivatives catalyst. Tetrahedron, 2006. 62(10): p. 2388-2394.
  51. Enders, D. and H. Schubert, Enantioselective Synthesis of β-Substituted Primary Amines; α-Alkylation/Reductive Amination of Aldehydes via SAMP-
  52. Nagel, U., E. Kinzel, J. Andrade, and G. Prescher, Enantioselektive Katalyse, 4. Synthese N-substituierter (R,R)-3,4-Bis(diphenylphosphino)- pyrrolidine und Anwendung ihrer Rhodiumkomplexe zur asymmetrischen Hydrierung von α-(Acylamino)acrylsäure-Derivaten. Chemische Berichte, 1986. 119(11): p. 3326-3343.
  53. Enders, D. and H. Schubert, Enantioselektive Synthese von β-substituierten primären Amine; α-Alkylierung/reduktive Aminierung von Aldehyden via SAMP-Hydrazone. Angewandte Chemie, 1984. 96(5): p. 368-369.
  54. Padwa, A. and S. Murphree, Epoxides and aziridines -A mini review. ARKIVOC, 2006. 3: p. 6-33. 97. Argouarch, G., G. Stones, C. Gibson, A. Kennedy, and D. Sherrington, Biflurcated, modular syntheses of chiral annulet triazacyclononanes. Org. Biomol.Chem, 2003. 1: p. 4408-4417.
  55. Jalaie, E. Zhang, and J.J. Edmunds, Equipotent activity in both enantiomers of a series of ketopiperazine-based renin inhibitors. Bioorganic & Medicinal Chemistry Letters, 2005. 15(9): p. 2371-2374.
  56. Rawlings, N.D. and A.J. Barrett, Evolutionary families of peptidases. Biochem. J., 1993. 290(1): p. 205-218.
  57. Lipinski, C.A., F. Lombardo, B.W. Dominy, and P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 1997. 23(1-3): p. 3-25.
  58. Skerlj, R.T., S. Nan, Y. Zhou, and G.J. Bridger, Facile synthesis of a selectively protected triazamacrocycle. Tetrahedron Letters, 2002. 43(42): p. 7569-7571.
  59. Cossy, J., C. Dumas, P. Michel, and D.G. Pardo, Formation of optically active 3-hydroxypiperidines. Tetrahedron Letters, 1995. 36(4): p. 549-552.
  60. Geburtsort: Bergisch Gladbach Staatsangehörigkeit: deutsch
  61. Mikata, Y., Y. Inaba, M. Morioka, and S. Yano, General synthesis of sugar- pendant 1,3-propanediamines containing a C-glycoside linkage. Tetrahedron Letters, 2004. 45(48): p. 8785-8788.
  62. INC.AMGEN, Heterocyclic Modulators of PKB, in Espacenet. 2009. p. 131-132.
  63. Feng, B.Y., A. Shelat, T.N. Doman, R.K. Guy, and B.K. Shoichet, High- throughput assays for promiscuous inhibitors. Nat Chem Biol, 2005. 1(3): p. 146-148.
  64. Hyland, L.J., T.A. Tomaszek, and T.D. Meek, Human immunodeficiency virus-1 protease. 2. Use of pH rate studies and solvent kinetic isotope effects to elucidate details of chemical mechanism. Biochemistry, 1991. 30(34): p. 8454-8463.
  65. Dann, J.G., D.K. Stammers, C.J. Harris, R.J. Arrowsmith, D.E. Davies, G.W. Hardy, and J.A. Morton, Human renin: A new class of inhibitors. Biochemical and Biophysical Research Communications, 1986. 134(1): p. 71-77.
  66. Abdel-Meguid, S.S., Inhibitors of Aspartyl Proteinases. Medicinal Research Reviews, 1993. 13(6): p. 731-778.
  67. Krake, S.H. and S.C. Bergmeier, Inter-and intramolecular reactions of epoxides and aziridines with π-nucleophiles. Tetrahedron, 2010. 66(37): p. 7337-7360.
  68. Smith, R., I. Brereton, M.,, R. Chai, Y.,, and S.B. Kent, Ionization states of the catalytic residues in HIV-1 protease. Nature Structural Biology, 1996. 3(11): p. 946-950.
  69. Ido, E., H.P. Han, F.J. Kezdy, and J. Tang, Kinetic studies of human immunodeficiency virus type 1 protease and its active-site hydrogen bond mutant A28S. Journal of Biological Chemistry, 1991. 266(36): p. 24359-66.
  70. Gohlke, H., M. Hendlich, and G. Klebe, Knowledge-based scoring function to predict protein-ligand interactions. Journal of Molecular Biology, 2000. 295(2): p. 337-356.
  71. Reynolds, C.H., B.A. Tounge, and S.D. Bembenek, Ligand Binding Efficiency: Trends, Physical Basis, and Implications. Journal of Medicinal Chemistry, 2008. 51(8): p. 2432-2438.
  72. Bembenek, S.D., B.A. Tounge, and C.H. Reynolds, Ligand efficiency and fragment-based drug discovery. Drug Discovery Today, 2009. 14(5-6): p. 278-283.
  73. Hopkins, A.L., C.R. Groom, and A. Alex, Ligand efficiency: a useful metric for lead selection. Drug Discovery Today, 2004. 9(10): p. 430-431. 130.
  74. Marciniszyn, J., J.A. Hartsuck, and J. Tang, Mode of inhibition of acid proteases by pepstatin. Journal of Biological Chemistry, 1976. 251(22): p. 7088-7094.
  75. Babine, R.E. and S.L. Bender, Molecular Recognition of Protein-Ligand Complexes: Applications to Drug Design. Chemical Reviews, 1997. 97(5): p. 1359-1472.
  76. Horimoto, Y., D.R. Dee, and R.Y. Yada, Multifunctional aspartic peptidase prosegments. New Biotechnology, 2009. 25(5): p. 318-324.
  77. Pauling, L., Nature of forces between large molecules of biological interest. Nature, 1948. 161: p. 707-709.
  78. Procopio, A., S. Alcaro, A. De Nino, L. Maiuolo, F. Ortuso, and G. Sindona, New conformationally locked bicyclic N,O-nucleoside analogues of antiviral drugs. Bioorganic & Medicinal Chemistry Letters, 2005. 15(3): p. 545- 550.
  79. Yamazaki, T., L.K. Nicholson, P. Wingfield, S.J. Stahl, J.D. Kaufman, C.J. Eyermann, C.N. Hodge, P.Y.S. Lam, and D.A. Torchia, NMR and X-ray Evidence That the HIV Protease Catalytic Aspartyl Groups Are Protonated in the Complex Formed by the Protease and a Non-Peptide Cyclic Urea- Based Inhibitor. Journal of the American Chemical Society, 1994. 116(23): p. 10791-10792.
  80. Szelke, On the rational design of renin inhibitors: x-ray studies of aspartic proteinases complexed with transition-state analogs. Biochemistry, 1987. 26(18): p. 5585-5590. 38. Bursavich, M.G. and D.H. Rich, Designing Non-Peptide Peptidomimetics in the 21st Century: Inhibitors Targeting Conformational Ensembles. Journal of Medicinal Chemistry, 2002. 45(3): p. 541-558.
  81. Teramoto, T., M. Deguchi, T. Kurosaki, and M. Okawara, Optically active N-hydroxytartrimides for enantioselective peptide synthesis. Tetrahedron Letters, 1981. 22(12): p. 1109-1112.
  82. Dunn, B., Overview of Pepsin-like Aspartic Peptidases. Current Protocols in Protein Science, 2001. 21.3(25): p. 21.3.1-21.3.6.
  83. Umezawa, H., T. Aoyagi, H. Morishima, M. Matsuzaki, and M. Hamada, Pepstatin, a new pepsin inhibitor produced by Actinomycetes. The Journal of Antibiotics, 1970. 23(5): p. 259-262. 43. Charles, F., Drug Therapy: HIV-Protease Inhibitors. The New England Journal of Medicine, 1998. 338(18): p. 1281-1292.
  84. Bartlett, P.A. and W.B. Kezer, Phosphinic acid dipeptide analogs: potent, slow-binding inhibitors of aspartic peptidases. Journal of the American Chemical Society, 1984. 106(15): p. 4282-4283.
  85. Güller, R., A. Binggeli, V. Breu, D. Bur, W. Fischli, G. Hirth, C. Jenny, M. Kansy, F. Montavon, M. Müller, C. Oefner, H. Stadler, E. Vieira, M. Wilhelm, W. Wostl, and H.P. Märki, Piperidine-renin inhibitors compounds with improved physicochemical properties. Bioorganic & Medicinal Chemistry Letters, 1999. 9(10): p. 1403-1408.
  86. Roth, K., Polymorphie: Fast ein kristallographisches Wintermärchen. Chemie in unserer Zeit, 2006. 40(6): p. 398-406.
  87. Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3 rd ed. 1999: JOHN WILEY & SONS, INC. 106.
  88. Lam, P.Y., P.K. Jadhav, C.J. Eyermann, C.N. Hodge, Y. Ru, L.T. Bacheler, J.L. Meek, M.J. Otto, M.M. Rayner, Y.N. Wong, and a. et, Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science, 1994. 263(5145): p. 380-384.
  89. Amundsen, L.H. and L.S. Nelson, Reduction of Nitriles to Primary Amines with Lithium Aluminum Hydride. Journal of the American Chemical Society, 1951. 73(1): p. 242-244.
  90. Oefner, C., A. Binggeli, V. Breu, D. Bur, J.P. Clozel, A. D'Arcy, A. Dorn, W. Fischli, F. Grüninger, R. Güller, G. Hirth, H.P. Märki, S. Mathews, M. Müller, R.G. Ridley, H. Stadier, E. Vieira, M. Wilhelm, F.K. Winkler, and W. Wostl, Renin inhibition by substituted piperidines: A novel paradigm for the inhibition of monomeric aspartic proteinases? Chemistry & Biology, 1999. 6(3): p. 127-131. 7 LITERATURVERZEICHNIS 59. Powell, N.A., E.H. Clay, D.D. Holsworth, J.W. Bryant, M.J. Ryan, M.
  91. Cossy, J., C. Dumas, and D.G. Pardo, Ring Expansion – Formation of Optically Active 3-Hydroxypiperidines from Pyrrolidinemethanol Derivatives. European Journal of Organic Chemistry, 1999. 1999(7): p. 1693-1699.
  92. Bauer, J., S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, and J. Morris, Ritonavir: An Extraordinary Example of Conformational Polymorphism. Pharmaceutical Research, 2001. 18(6): p. 859-866. 128.
  93. Noble, S. and D. Faulds, Saquinavir: A Review of its Pharmacology and Clinical Potential in the Management of HIV Infection. Drugs, 1996. 52(1): p. 93-112.
  94. Gololobov, Y.G., I.N. Zhmurova, and L.F. Kasukhin, Sixty years of staudinger reaction. Tetrahedron, 1981. 37(3): p. 437-472.
  95. Cremlyn, R.J.W., Some reactions of O,O-diphenylphosphoryl azide. Australian Journal of Chemistry, 1973. 26(7): p. 1591-1593.
  96. Torrado, A., Stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres. Tetrahedron Letters, 2006. 47(39): p. 7097-7100.
  97. Pierce, M.E., G.D. Harris, Q. Islam, L.A. Radesca, L. Storace, R.E. Waltermire, E. Wat, P.K. Jadhav, and G.C. Emmett, Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323. The Journal of Organic Chemistry, 1996. 61(2): p. 444-450.
  98. Haefliger, W. and E. Klöppner, Stereospezifische Synthese einer neuen Morphin-Teilstruktur. Helvetica Chimica Acta, 1982. 65(6): p. 1837-1852. 118. Staudinger, H. and J. Meyer, Über neue organische Phosphorverbindungen III. Phosphinmethylenderivate und Phosphinimine. Helvetica Chimica Acta, 1919. 2(1): p. 635-646.
  99. Dunn, B.M., Structure and Mechanism of the Pepsin-Like Family of Aspartic Peptidases. Chemical Reviews, 2002. 102(12): p. 4431-4458. 19. Tang, J., M.N.G. James, I.N. Hsu, J.A. Jenkins, and T.L. Blundell, Structural evidence for gene duplication in the evolution of the acid proteases. Nature, 1978. 271(5646): p. 618-621.
  100. Holloway, M.K., P. Hunt, and G.B. McGaughey, Structure and modeling in the design of β-and γ-secretase inhibitors. Drug Development Research, 2009. 70(2): p. 70-93.
  101. Jensen, E. O'Brien, A. Stanton, and M.P. Bedigian, Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochemical and Biophysical Research Communications, 2003. 308(4): p. 698-705.
  102. Rahuel, J., V. Rasetti, J. Maibaum, H. Rüeger, R. Göschke, N.C. Cohen, S. Stutz, F. Cumin, W. Fuhrer, J.M. Wood, and M.G. Grütter, Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin. Chemistry & Biology, 2000. 7(7): p. 493-504.
  103. Blum, A., Böttcher, J., Heine, A., Klebe, G., Diederich, W.E., Structure- Guided Design of C2-Symmetric HIV-1 Protease Inhibitors Based on a Pyrrolidine Scaffold. Journal of Medicinal Chemistry, 2008. 51: p. 2078- 2087. 66. Rich, D.H., M.G. Bursavich, and M.A. Estiarte, Discovery of nonpeptide, peptidomimetic peptidase inhibitors that target alternate enzyme active site conformations. Peptide Science, 2002. 66(2): p. 115-125.
  104. Vieira, E., A. Binggeli, V. Breu, D. Bur, W. Fischli, R. Güller, G. Hirth, H.P. Märki, M. Müller, C. Oefner, M. Scalone, H. Stadler, M. Wihelm, and W. Wostl, Substituted piperidines -highly potent renin inhibitors due to induced fit adaptation of the active site. Bioorganic & Medicinal Chemistry Letters, 1999. 9(10): p. 1397-1402.
  105. Institut für Pharmakologie und Institut für Organische Chemie, Universität zu Köln Diplomarbeit: " Synthese von Cyclo(Arginin-Prolin) und Cyclo(Lysin-Prolin) und die Bestimmung deren Transporteffizienzen mit den humanen organischen Kationentransportern OCT1, OCT2 und EMT " 10. 2001 – 08. 2007 RWTH Aachen und Universität zu Köln Studium der Chemie, Abschluss als Diplom-Chemikerin 08. 1992 – 07. 2001
  106. Silbernagel, S., Despopoulos, A., Taschenatlas der Physiologie. 6.korrigierte Auflage ed. 2003: Thieme. 7 LITERATURVERZEICHNIS 35. Hofbauer, K.G. and J.M. Wood, Renin inhibitors as possible antihypertensive agents. Journal of Molecular Medicine, 1988. 66(18): p. 906-913.
  107. Pearl, L. and T. Blundell, The active site of aspartic proteinases. FEBS Letters, 1984. 174(1): p. 96-101.
  108. Heine, H.W., W.G. Kenyon, and E.M. Johnson, The Isomerization and Dimerization of Aziridine Derivatives. IV. Journal of the American Chemical Society, 1961. 83(11): p. 2570-2574.
  109. Job, A., C.F. Janeck, W. Bettray, R. Peters, and D. Enders, The SAMP- /RAMP-hydrazone methodology in asymmetric synthesis. Tetrahedron, 2002. 58(12): p. 2253-2329.
  110. Davies, D.R., The Structure and Function of the Aspartic Proteinases. Annual Review of Biophysics and Biophysical Chemistry, 1990. 19(1): p. 189-215.
  111. Kovacková, S., M. Dracínský, and D. Rejman, The synthesis of piperidine nucleoside analogs -a comparison of several methods to access the introduction of nucleobases. Tetrahedron, 2011. 67(7): p. 1485-1500. 147. Reynolds, C.H., S.D. Bembenek, and B.A. Tounge, The role of molecular size in ligand efficiency. Bioorganic & Medicinal Chemistry Letters, 2007. 17(15): p. 4258-4261.
  112. Klebe, G., Wirkstoffdesign -Entwicklung und Wirkung von Arzneistoffen. 2 ed. 2009: Spektrum. 381-402.
  113. Bräse, S., C. Gil, K. Knepper, and V. Zimmermann, Organic Azides: An Exploding Diversity of a Unique Class of Compounds. Angewandte Chemie International Edition, 2005. 44(33): p. 5188-5240.
  114. Coombs, G.H., D.E. Goldberg, M. Klemba, C. Berry, J. Kay, and J.C. Mottram, Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends in Parasitology, 2001. 17(11): p. 532-537.
  115. Enders, D. and L. Wortmann, Asymmetric Synthesis of 4,6-Disubstituted 1,2,3,4,5,6-Hexahydro-5-hydroxypyrimidin-2-ones as Potential HIV- Protease-Inhibitors. Heterocycles, 2002. 58(1): p. 293-299.
  116. Spitzmüller, A., H.F.G. Velec, and G. Klebe, MiniMuDS: A New Optimizer using Knowledge-Based Potentials Improves Scoring of Docking Solutions. Journal of Chemical Information and Modeling, 2011. 51(6): p. 1423-1430.
  117. Chooi, S.Y.M., P.-h. Leung, S.-c. Ng, G.H. Quek, and K.Y. Sim, A simple route to optically pure 2,3-diaminobutane. Tetrahedron: Asymmetry, 1991. 2(10): p. 981-982.
  118. Kuntz, I.D., K. Chen, K.A. Sharp, and P.A. Kollaman, The maximal affinity of ligands. PNAS, 1999. 96: p. 9997-10002.
  119. Trylska, J., J. Antosiewicz, M. Geller, C.N. Hodge, R.M. Klabe, M.S. Head, and M.K. Gilson, Thermodynamic linkage between the binding of protons and inhibitors to HIV-1 protease. Protein Science, 1999. 8(1): p. 180-195.
  120. Ingr, M., T.á. Uhlíková, K. Str̆ ís̆ ovský, E. Majerová, and J. Konvalinka, Kinetics of the dimerization of retroviral proteases: The " fireman's grip " and dimerization. Protein Science, 2003. 12(10): p. 2173-2182.
  121. Li, M., F. DiMaio, D. Zhou, A. Gustchina, J. Lubkowski, Z. Dauter, D. Baker, and A. Wlodawer, Crystal structure of XMRV protease differs from the structures of other retropepsins. Nat Struct Mol Biol, 2011. 18(2): p. 227-229.
  122. Chandler, B.D., J.T. Roland, Y. Li, and E.J. Sorensen, Seebach's Conjunctive Reagent Enables Double Cyclizations. Organic Letters, 2010. 12(12): p. 2746-2749.
  123. Gallo, Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proceedings of the National Academy of Sciences, 1980. 77(12): p. 7415- 7419.
  124. Blum, A., J. Böttcher, B. Sammet, T. Luksch, A. Heine, G. Klebe, and W.E. Diederich, Achiral oligoamines as versatile tool for the development of aspartic protease inhibitors. Bioorganic & Medicinal Chemistry, 2008. 16(18): p. 8574-8586.
  125. Busto, E., V. Gotor-Fernández, J. Montejo-Bernardo, S. García-Granda, and V. Gotor, Development of a chemoenzymatic strategy for the synthesis of optically active and orthogonally protected polyamines. Tetrahedron, 2009. 65(40): p. 8393-8401.
  126. Amzel, L.M., Structure-based drug design. Current Opinion in Biotechnology, 1998. 9(4): p. 366-369. 255
  127. Dominguez, D.-I., Hartmann, D., De Strooper, B., BACE1 and Presenilin: Two Unusual Aspartyl Proteases Involved in Alzheimer's Disease. Neurodegenerative Diseases, 2004. 1(4-5): p. 168-174.

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