Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement

Journal of Medicinal Chemistry

Volumn 52, Issue 22, 2009, Pages 7069-7080

  Buchholz, Mirko ^a   Hamann, Antje ^a   Aust, Susanne ^a   Brandt, Wolfgang ^b   Böhme, Livia ^a   Hoffmann, Torsten ^a   Schilling, Stephan ^a   Demuth, Hans Ulrich ^a   Heiser, Ulrich ^a  

^a PROBIODRUG AG   (Germany)

^b LEIBNIZ INSTITUTE OF PLANT BIOCHEMISTRY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

1 TRITYL 3 [3 (1,3 DIOXO 1,3 DIHYDRO 2H ISOINDOL 2 YL)PROPYL] 1,4 DIMETHYL 1H IMIDAZOL 3 IUM BROMIDE; 2 (3 (4 METHYL 1H IMIDAZOL 1 YL)PROPYL)ISOINDOLINE 1,3 DIONE; 2 (3 (4/5 METHYL 1H IMIDAZOL 1 YL)PROPYL)ISOINDOLINE 1,3 DIONE; 2 (3 (5 METHYL 1H IMIDAZOL 1 YL)PROPYL)ISOINDOLINE 1,3 DIONE; 3 (4 METHYL 1H IMIDAZOL 1 YL)PROPAN 1 AMINE; 3 (5 METHYL 1H IMIDAZOL 1 YL)PROPAN 1 AMINE; 3(5 METHYL 1H IMIDAZOL 1 YL)PROPAN 1 AMINE; 4 METHYL 1 TRITYL 1H IMIDAZOLE; AMYLOID BETA PROTEIN; ENZYME; GLUTAMINYL CYCLASE; UNCLASSIFIED DRUG;

ARTICLE; CELL CULTURE; CHEMICAL STRUCTURE; CONTROLLED STUDY; DRUG EFFICACY; EMBRYO; ENZYME ACTIVE SITE; HUMAN; HUMAN CELL; INTROSPECTION; METAL BINDING; MODEL; MONITORING;

AMINOACYLTRANSFERASES; AMYLOID BETA-PROTEIN; CATALYTIC DOMAIN; CELL LINE; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; MODELS, MOLECULAR; PYRROLIDONECARBOXYLIC ACID; STRUCTURE-ACTIVITY RELATIONSHIP; THIOUREA;

EID: 70949097595     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900969p     Document Type: Article

References (49)

1. Awade, A. C.; Cleuziat, P.; Gonzales, T.; Robert-Baudouy, J. Pyrrolidone carboxyl peptidase (Pcp): an enzyme that removes pyroglutamic acid (pGlu) from pGlu-peptides and pGlu-proteins. Proteins 1994, 20, 34-51. (Pubitemid 24308148)
2. Abraham, G. N.; Podell, D. N. Pyroglutamic acid. Non-metabolic formation, function in proteins and peptides, and characteristics of the enzymes effecting its removal. Mol. Cell. Biochem. 1981, 38, 181-190.
3. Van Coillie, E.; Proost, P.; Van, A., I; Struyf, S.; Polfliet, M.; De, M., I; Harvey, D. J.; Van Damme, J.; Opdenakker, G. Functional comparison of two human monocyte chemotactic protein-2 isoforms, role of the amino-terminal pyroglutamic acid and processing by CD26/dipeptidyl peptidase IV. Biochemistry 1998, 37, 12672-12680. (Pubitemid 28427552)
4. Busby, W. H.; Humm, J.; Kizer, J. S.; Youngblood, W. W.; Quackenbush, G. An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. J. Biol. Chem. 1987, 262, 8532-8536.
5. Messer, M.; Ottesen, M. Isolation and properties of glutamine cyclotransferase of dried papaya latex. Biochim. Biophys. Acta 1964, 92, 409-411.
6. Fischer, W. H.; Spiess, J. Identification of a mammalian glutaminyl cyclase converting glutaminyl into pyroglutamyl peptides. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 3628-3632.
7. Pohl, T.; Zimmer, M.; Mugele, K.; Spiess, J. Primary structure and functional expression of a glutaminyl cyclase. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 10059-10063.
8. Fraser, L. R. Fertilization promoting peptide: an important regulator of sperm function in vivo? Rev. Reprod. 1998, 3, 151-154. (Pubitemid 28508645)
9. Schilling, S.; Niestroj, A. J.; Rahfeld, J.U.; Hoffmann, T.; Wermann, M.; Zunkel, K.; Wasternack, C.; Demuth, H.-U. Identification of human glutaminyl cyclase as a metalloenzyme. Potent inhibition by imidazole derivatives and heterocyclic chelators. J. Biol. Chem. 2003, 278, 49773-49779.
10. Bateman, R. C., Jr.; Temple, J. S.; Misquitta, S. A.; Booth, R. E. Evidence for essential histidines in human pituitary glutaminyl cyclase. Biochemistry 2001, 40, 11246-11250.
11. Schilling, S.; Manhart, S.; Hoffmann, T.; Ludwig, H.-H.; Wasternack, C.; Demuth, H.-U. Substrate specifity of glutaminyl cyclases from plants and animals. Biol. Chem. 2003, 384, 1583-1592.
12. Booth, R. E.; Lovell, S. C.; Misquitta, S. A.; Bateman, R. C., Jr. Humanglutaminyl cyclase and bacterial zinc aminopeptidase share a common fold and active site. BMC Biol. 2004, 2, 2.
13. Huang, K. F.; Liu, Y. L.; Cheng, W. J.; Ko, T. P.; Wang, A. H. Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13117-13122.
14. Huang, K. F.; Liu, Y. L.; Wang, A. H. Cloning, expression, characterization, and crystallization of a glutaminyl cyclase from human bone marrow: a single zinc metalloenzyme. Protein Expression Purif. 2005, 43, 65-72.
15. Song, I.; Temple, J. S.; Burns, K. H.; Bateman, R. C., Jr. Absence of an essential thiol in human glutaminyl cyclase: implications for mechanism. Korean J. Biol. Sci. 1998, 2, 243-248.
16. Cynis, H.; Rahfeld, J. U.; Stephan, A.; Kehlen, A.; Koch, B.; Wermann, M.; Demuth, H.-U.; Schilling, S. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J. Mol. Biol. 2008, 379, 966-980.
17. Bockers, T. M.; Kreutz, M. R.; Pohl, T. Glutaminyl-cyclase expression in the bovine/porcine hypothalamus and pituitary. J. Neuroendocrinol. 1995, 7, 445-453.
18. Saido, T. C.; Iwatsubo, T.; Mann, D. M.; Shimada, H.; Ihara, Y.; Kawashima, S. Dominant and differential deposition of distinct beta-amyloid peptide species, A beta N3(pE), in senile plaques. Neuron 1995, 14, 457-466.
19. Schilling, S.; Zeitschel, U.; Hoffmann, T.; Heiser, U.; Francke, M.; Kehlen, A.; Holzer, M.; Hutter-Paier, B.; Prokesch, M.; Windisch, M.; Jagla, W.; Schlenzig, D.; Lindner, C.; Rudolph, T.; Reuter, G.; Cynis, H.; Montag, D.; Demuth, H.-U.; Rossner, S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat. Med. 2008, 14, 1106-1111.
20. Miravalle, L.; Calero, M.; Takao, M.; Roher, A. E.; Ghetti, B.; Vidal, R. Amino-terminally truncated Abeta peptide species are the main component of cotton wool plaques. Biochemistry 2005, 44, 10810-10821. (Pubitemid 41153641)
21. Schilling, S.; Hoffmann, T.; Manhart, S.; Hoffmann, M.; Demuth, H.-U. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004, 563, 191-196.
22. Schilling, S.; Lauber, T.; Schaupp, M.; Manhart, S.; Scheel, E.; Bohm, G.; Demuth, H.-U. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry 2006, 45, 12393-12399.
23. Youssef, I.; Florent-Bechard, S.; Malaplate-Armand, C.; Koziel, V.; Bihain, B.; Olivier, J. L.; Leininger-Muller, B.; Kriem, B.; Oster, T.; Pillot, T. N-Truncated amyloid-beta oligomers induce learning impairment and neuronal apoptosis. Neurobiol. Aging 2007, 29, 1319-1333. (Pubitemid 351981997)
24. Russo, C.; Violani, E.; Salis, S.; Venezia, V.; Dolcini, V.; Damonte, G.; Benatti, U.; D'Arrigo, C.; Patrone, E.; Carlo, P.; Schettini, G. Pyroglutamate-modified amyloid beta-peptides - AbetaN3(pE) - strongly affect cultured neuron and astrocyte survival. J. Neurochem. 2002, 82, 1480-1489.
25. Schilling, S.; Appl, T.; Hoffmann, T.; Cynis, H.; Schulz, K.; Jagla, W.; Friedrich, D.; Wermann, M.; Buchholz, M.; Heiser, U.; von Horsten, S.; Demuth, H.-U. Inhibition of glutaminyl cyclase prevents pGlu-Abeta formation after intracortical/hippocampal microinjection in vivo/in situ. J. Neurochem. 2008, 106, 1225-1236.
26. Buchholz, M.; Heiser, U.; Schilling, S.; Niestroj, A. J.; Zunkel, K.; Demuth, H.-U. The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship. J. Med. Chem. 2006, 49, 664-677.
27. Thornber, C. W. Isosterism and molecular modification in drug design. Chem. Soc. Rev. 1979, 8, 563-580.
28. Patani, G. A.; LaVoie, E. J. Bioisosterism: a rational approach in drug design. Chem. Rev. 1996, 96, 3147-3176.
29. Lima, L. M.; Barreiro, E. J. Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem. 2005, 12, 23-49.
30. Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Miles, P. D.; Parsons, M. E.; Prain, H. D.; White, G. R. Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine. J. Med. Chem. 1977, 20, 901-906.
31. Duncan, W. A.; Parsons, M. E. Reminiscences of the development of cimetidine. Gastroenterology 1980, 78, 620-625.
32. Atwal, K. S.; Ahmed, S. Z.; O'Reilly, B. C. A facile synthesis of cyanoguanidines from thioureas. Tetrahedron Lett. 1989, 30, 7313-7316.
33. Stankovic, S.; Skobaljic, N.; Stojanovic, N.; Stojicic, S. Procedure for Synthesis of N-[2[[[5-[(Dialkylamino)methyl]-2-furanyl]-methyl]thyo]ethyl]- N′-alkyl-2-nitro-1,1-alkenediamines and Their Hydrochlorides. PCT/YU99/00011, 2000; pp 1-11.
34. Shirotani, K.; Tsubuki, S.; Lee, H. J.; Maruyama, K.; Saido, T. C. Generation of amyloid beta peptide with pyroglutamate at position 3 in primary cortical neurons. Neurosci. Lett. 2002, 327, 25-28.
35. Cynis, H.; Scheel, E.; Saido, T. C.; Schilling, S.; Demuth, H.-U. Amyloidogenic processing of amyloid precursor protein: evidence of a pivotal role of glutaminyl cyclase in generation of pyroglutamate-modified amyloid-beta. Biochemistry 2008, 47, 7405-7413.
36. Henikoff, S.; Henikoff, J. G. Amino acid substitution matrices from protein blocks. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 10915-10919.
37. Schilling, S.; Cynis, H.; von Bohlen, A.; Hoffmann, T.; Wermann, M.; Heiser, U.; Buchholz, M.; Zunkel, K.; Demuth, H.-U. Isolation, catalytic properties, and competitive inhibitors of the zinc-dependent murine glutaminyl cyclase. Biochemistry 2005, 44, 13415-13424.
38. Prescott, J. M.; Wagner, F. W.; Holmquist, B.; Vallee, B. L. Spectral and kinetic studies of metal-substituted Aeromonas aminopeptidase: nonidentical, interacting metal-binding sites. Biochemistry 1985, 24, 5350-5356.
39. Bayliss, M. E.; Prescott, J. M. Modified activity of Aeromonas aminopeptidase: metal ion substitutions and role of substrates. Biochemistry 1986, 25, 8113-8117.
40. Chevrier, B.; Schalk, C.; D'Orchymont, H.; Rondeau, J. M.; Moras, D.; Tarnus, C. Crystal structure of Aeromonas proteolytica aminopeptidase: a prototypical member of the co-catalytic zinc enzyme family. Structure 1994, 2, 283-291. (Pubitemid 124001625)
41. Cole, J. C.; Nissink, W. M.; Taylor, R. Protein-Ligand Docking and Virtual Screening with GOLD. In Virtual Screening in Drug Discovery; Alvarez, J., Shoichet, S., Eds.; Taylor & Francis: Boca Raton, FL, 2005; pp 379-415.
42. Ajay; Murcko, M. A. Computational methods to predict binding free energy in ligand-receptor complexes. J. Med. Chem. 1995, 38, 4953-4967.
43. a Values of Small and Large Molecules. http://www.chemaxon.com/conf/Calculating- pKa-values-of-small-and-large-molecules.pdf (2009); ChemAxon.
44. Schilling, S.; Hoffmann, T.; Wermann, M.; Heiser, U.; Wasternack, C.; Demuth, H.-U. Continuous spectrometric assays for glutaminyl cyclase activity. Anal. Biochem. 2002, 303, 49-56.
45. Schilling, S.; Hoffmann, T.; Rosche, F.; Manhart, S.; Wasternack, C.; Demuth, H.-U. Heterologous expression and characterization of human glutaminyl cyclase: evidence for a disulfide bond with importance for catalytic activity. Biochemistry 2002, 41, 10849-10857.
46. Sippl, M. J. Recognition of errors in three-dimensional structures of proteins. Proteins 1993, 17, 355-362. (Pubitemid 23358545)
47. Hendlich, M.; Lackner, P.; Weitckus, S.; Floeckner, H.; Froschauer, R.; Gottsbacher, K.; Casari, G.; Sippl, M. J. Identification of native protein folds amongst a large number of incorrect models. The calculation of low energy conformations from potentials of mean force. J. Mol. Biol. 1990, 216, 167-180.
48. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 1993, 26, 283-291.
49. Pellegrini, E.; Field, M. J. A generalized-Born solvation model for macromolecular hybrid-potential calculations. J. Phys. Chem. A 2002, 106, 1316-1326.