Azepanone-based inhibitors of human cathepsin L

Journal of Medicinal Chemistry

Volumn 48, Issue 22, 2005, Pages 6870-6878

  Marquis, Robert W ^a   James, Ian ^a,b   Zeng, Jin ^a   Trout, Robert E Lee ^a   Thompson, Scott ^a   Rahman, Attiq ^a   Yamashita, Dennis S ^a   Xie, Ren ^a   Ru, Yu ^a   Gress, Catherine J ^a,b   Blake, Simon ^a,b   Lark, Michael A ^a,b   Hwang, Shing Mei ^a   Tomaszek, Thaddeus ^a   Offen, Priscilla ^a   Head, Martha S ^a   Cummings, Maxwell D ^a,c   Veber, Daniel F ^a,d  

^a GLAXOSMITHKLINE   (United States)

^b CENTOCOR INC   (United States)

^c JOHNSON AND JOHNSON PHARMACEUTICAL RESEARCH AND DEVELOPMENT   (United States)

^d NONE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE DERIVATIVE; AMIDE; AZEPANONE; AZEPINE DERIVATIVE; BETA NAPHTHYLALANINE; CATHEPSIN K; CATHEPSIN L; ENZYME INHIBITOR; LEUCINE; NAPHTHALENE 2 CARBOXYLIC ACID[2 NAPHTHALEN 2 YL 1 [3 OXO 1 (PYRIDINE 2 SULFONYL)AZEPAN 4 YLCARBAMOYL]ETHYL]AMIDE; NAPHTHYLENE 1 CARBOXAMIDE; PHENYLALANINE; QUINOLINE 8 CARBOXAMIDE; UNCLASSIFIED DRUG;

AMINO ACID SUBSTITUTION; ARTICLE; COMPETITIVE INHIBITION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; DRUG SYNTHESIS; ELECTROSPRAY MASS SPECTROMETRY; ENZYME ACTIVE SITE; MOLECULAR MODEL; PROTON NUCLEAR MAGNETIC RESONANCE; REACTION ANALYSIS; STRUCTURE ACTIVITY RELATION;

AMIDES; AZEPINES; BINDING SITES; CATHEPSINS; CYSTEINE ENDOPEPTIDASES; CYSTEINE PROTEINASE INHIBITORS; HUMANS; MODELS, MOLECULAR; QUINOLINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 27444434253     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm0502079     Document Type: Article

References (38)

1. (a) Venter, C. J.; et al. The sequence of the human genome. Science 2001, 291, 1304-1351.
2. (b) Lander, E. S.; et al. Initial sequencing and analysis of the human genome. Nature 2001, 409, 860-921.
3. (c)Brömme, D.; Kaleta. Thiol-depedent cathepsins: Pathophysiological implications and recent advances in inhibitor design. J. Curr. Pharm. Des. 2002, 8, 1639-1658.
4. (a) Marquis, R. W. Inhibition of the cystiene protease cathepsin K. Ann. Rep. Med. Chem. 2004, 39, 79-98.
5. (b) Deaton, D. N.; Kumar, S. Prog. Med. Chem. 2004, 42, 245-375.
6. (c) Veber, D. F.; Drake, F. H.; Gowen, M. The new partnership of genomics and chemistry for accelerated drug discovery. Curr. Opin. Chem. BM. 1997, 1, 151-156.
7. Marquis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.; Yamashita, D. S.; Oh, H.-J.; Erhard, K. E.; Davis, L. D.; Tomaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.; Ward, K.; Smith, B.; Levy, M.; Cummings, M. D.; Haltiwanger, R. C.; Trescher, G.; Wang, B.; Hemling, M. E.; Quinn, C. J.; Cheng, H.-Y.; Lin, F.; Smith, W. W.; Janson, C. A.; Zhao, B.; McQueney, M. S.; D'Alessio, K.; Lee, C.-P.; Marzulli, A.; Dodds, R. A.; Blake, S.; Hwang, S.-M.; James, I. E.; Gress, C. J.; Bradley, B. R.; Lark, M. W.; Gowen, M.; Veber, D. F. Azepanone-based inhibitors of human and rat cathepsin K. J. Med. Chem. 2001, 44, 1380-1395.
8. (a) Turk, B.; Turk, D.; Turk, V. Lysosomal cysteine proteases: More than scavengers. Biochim. Biophys. Acta 2000, 1477, 98-11.
9. (b) Kirschke, H.; Langner, J.; Wiederranders, B.; Ansorge, S.; Bohley, P.; Cathepsin, L. A new proteinase from rat-liver lysosomes. Eur. J. Biochem. 1977, 74, 293-301.
10. Nakagawa, T.; Roth, W.; Wong, P.; Nelson, A.; Farr, A.; Deussing, J.; Villadangos, J. A.; Ploegh, H.; Peters, C.; Rudensky, A. Y. Cathesin, L. Critical role in Ii degradation and CD4 T cell selection in the thymus. Science 1998, 280, 450-453.
11. Robker, R. L.; Russell, D. L.; Espey, L. L.; Lyndon, J. P.; O'Malley, B. W.; Richards, J. S. Progesterone-regulated genes in the ovulation process: ADAMTS-1 and cathepsin L proteases. Proc. Natl. Acad. Sci. 2000, 97, 4689-4694.
12. Kirschke, H.; Eerola, R.; Hopsu-Havu, V. K.; Brömme, D.; Vuorio, E. Antisense RNA inhibition of cathepsin L expression reduces tumorigenicity of malignant cells. Eur. J. Cancer 2000, 36, 787-795 and references therein.
13. Iwata, Y.; Mort, J. S.; Tateishi, H.; Lee, E. R. Macrophage cathepsin L, a factor in the erosion of subchondral bone in rheumatoid arthritis. Arthritis Rheum. 1997, 40, 499-509.
14. (a) Furuyama, N.; Fujisawa, Y. Distinct roles of cathepsin K and cathepsin L in osteoclastic bone resorption. Endocr. Res. 2000, 26, 189-204.
15. (b) Kakegawa, H.; Nikawa, T.; Kamioka, H.; Sumitani, K.; Kawata, T.; Drobnic-Kosorok, M.; Lenarcic, B.; Turk, V.; Katunuma, N. Participation of cathepsin L on bone resorption. FEBS Lett. 1993, 321, 247-250.
16. Benavides, F.; Venables, A.; Klug, H. P.; Glasscock, E.; Rudensky, A.; Gomez, M.; Palenzuela, N. M.; Guenet, J.-L.; Richie, E. R.; Conti, C. J. The CD4-T cell-deficient mouse mutation nackt (nkt) involves a deletion in the cathepsin L (Ctsl) gene. Immunogenetics 2001, 53, 233-242.
17. Potts, W.; Bowyer, J.; Jones, H.; Tucker, D.; Freemont, A. J.; Millest, A.; Martin, C.; Vernon, W.; Neerunjun, D.; Slynn, G.; Harper, F.; Maciewicz, R. Cathepsin-L deficient mice exhibit abnormal skin and bone development and show increased resistance to osteoporosis following ovariectomy. Int. J. Exp. Pathol. 2004, 85, 85-96.
18. (a) Woo, J.-T.; Yamaguchi, K.; Hayami, T.; Kobori, T.; Sigeizumi, S.; Sugimoto, K.; Kondo, K.; Tsuji, T.; Ohba, Y.; Tagami, K.; Sumitani, K. Suppresive effect of N-(benzyloxycarbonyl)-L-phenylalanyl-L-tyrosinal on bone resorption in vitro and in vivo. Eur. J. Pharmacol. 1996, 300, 131-135.
19. (b) Millest, A. J.; Breen, S. A.; Loveday, B. E.; Clarkson, P. N.; Sipson, C. A.; Waterton, J. C.; Johnstone, D. Effects of an inhibitor of cathepsin L on bone resorption in thyroparathroidectomized and ovariectomized rats. Bone 1997, 20, 465-471.
20. Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T. Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J. Med. Chem. 1998, 41, 4301-4308.
21. Stroup, G. B.; Lark, M. L.; Veber, D. F.; Bhattacharyya, A.; Blake, S.; Dare, L. C.; Erhard, K. F.; Hoffmann, S. J.; James, I. E.; Marquis, R. W.; Ru, Y.; Vasko-Moser, J. A.; Smith, B. R.; Tomaszek, T. A.; Gowen, M. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J. Bone Miner. Res. 2001, 16, 1739-1746.
22. (a) Mottram, J. C.; Brooks, D. R.; Coombs, G. H. Roles of cysteine proteinases of trypanosomes and Leishmania in host-parasite interactions. Curr. Opin. Microbiol. 1998, 1, 455.
23. (b) McKerrow, J. H.; McGrath, M. E.; Engel, J. C. The cysteine protease of Trypanasoma cruzi as a model for antiparasitic drug design. Parasitol. Today 1995, 11, 279-282.
24. Trout, R. E. L.; Marquis, R. W. Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K. Tetrahedron Lett. 2005, 46, 2799-2801.
25. James, I. E.; Lark, M. W.; Zembryki, D.; Lee-Rykaczewski, E. V.; Hwang, S.-M.; Tomaszek, T. A.; Belfiore, P.; Gowen, M. Development and characterization of a human in vitro resorption assay: Demonstration of utility using novel antiresorptive agents. J. Bone Miner. Res. 1999, 14, 1562-1569.
26. Dodds, R. A.; James, I. E.; Rieman, D.; Hwang, S.-M.; Ahern, R.; Conner, J. R.; Thompson, S.; Veber, D.; Drake, F. H.; Holmes, S.; Lark, M. W.; Gowen, M. Human osteoclast cathepsin K is processed intracellularly prior to attachment and bone resorption. J. Bone Miner. Res., 2001, 16, 478-486.
27. Definitive data for the presence of a similar intramolecular hydrogen bond was observed in the X-ray crystal structure of the closely related P3 quinoline-8-carboxamide 16.
28. Marquis, R. W.; Ru, Y.; Zeng, J.; Trout, R. E. L.; LoCastro, S. M.; Gribble, A. D.; Witherington, J.; Fenwick, A. E.; Garnier, B.; Tomaszek, T. A.; Tew, D.; Hemling, M. E.; Quinn, C. J.; Smith, W. W.; Zhao, B.; McQueney, M. S.; Janson, C. A.; D'Alessio, K.; Veber, D. F. Cyclic ketone inhibitors of the cysteine protease cathepsin K. J. Med. Chem. 2001, 44, 725-736.
29. Within these series, N-methylation of this amide N-H moiety resulted in significant losses of potency vs the cathepsins studied.
30. (a) Coulombe, R.; Grochulski, P.; Sivaraman, J.; Menard, R.; Mort, J. S.; Cygler, M. Structure of human procathepsin L reveals the molecular basis of inhibition of the prosegment. EMBO J. 1996, 15, 5492-5503.
31. (b) Groves, M. R.; Coulombe, R.; Jenkins, J.; Cygler, M. Structural basis for specificity of papain-like cysteine protease proregions toward their cognate enzymes proteins. Struct., Fund., Genet. 1998, 32, 504.
32. In the absence of X-ray cocrystal data of either 6 or 7 within the active site of cathepsin L, we are assuming that these inhibitors orient themselves on the unprimed side of the active site in a similar fashion as inhibitor 1 within the active site of cathepsin K. Additionally, we anticipate that the active site cysteine residue has added to the sterically more conjested re face of the ketone carbonyl moiety as was observed in the X-ray cocrystal structures of several azapanone-based inhibitors bound within the active site of cathepsin K.
33. Brömme, D.; Klaus, J. L.; Okamoto, K.; Rasnick, D.; Palmer, J. T. Peptidyl vinyl sulphones: A new class of potent and selective cysteine protease inhibitors. Biochem. J. 1996, 315, 85-89.
34. (a) McGrath, M. E.; Eakin, A. E.; Barnes, M. G.; Brömme, D. Crystal structure of human cathepsin K complexed with a potent inhibitor. Nat. Struct. Biol. 1997, 5, 104-109.
35. (b) Zhao, B.; Janson, C. A.; Amegadzie, B. Y.; D'Alessio, K.; Griffin, C.; Hanning, C. R.; Jones, C.; Kurdyla, J.; McQueney, M. S.; Qui, X.; Smith, W. W.; Abdel-Meguid, S. S.. Crystal structure of human osteoclast cathepsin K complex with E-64. Nat. Struct. Biol. 1997, 4, 109-111.
36. James, I. E.; Marquis, R. W.; Blake, S. M.; Hwang, S. M.; Gress, C. J.; Ru, Y.; Zembryki, D.; Yamashita, D. S.; McQueney, M. S.; Tomaszek, T. A.; Oh, H.-J.; Gowen, M.; Veber, D. F.; Lark, M. W. Potent and selective inhibitors of cathepsin L do not inhibit human osteoclast resorption in vitro. J. Biol. Chem. 2001, 276, 11507-11511.
37. A correction to ref 26 has been published. James, I. E.; Marquis, R. W.; Blake, S. M.; Hwang, S. M.; Gress, C. J.; Ru, Y.; Zembryki, D.; Yamashita, D. S.; McQueney, M. S.; Tomaszek, T. A.; Oh, H.-J.; Gowen, M.; Veber, D. F.; Lark, M. W. Potent and selective inhibitors of cathepsin L do not inhibit human osteoclast resorption in vitro. J. Biol. Chem. 2003, 278, 32484.
38. Our analysis of the selectivities of the potent cathepsin L peptide aldehyde inhibitors 16 and 17, reported in refs 12a and 13, respectively, revealed that these analogues were equally potent inhibitors of both cathepsins K and S in addition to the potent inhibition of cathepsin L. These results, which were not reported in the referenced accounts, suggests that the conclusions regarding the mode by which these inhibitors may have elicited their antiresorptive effect were ambiguous.