New α-substituted succinate-based hydroxamic acids as TNFα convertase inhibitors

Journal of Medicinal Chemistry

Volumn 42, Issue 23, 1999, Pages 4890-4908

  Barlaam, Bernard ^a   Bird, T Geoffrey ^a   Lambert Van Der Brempt, Christine ^a   Campbell, Douglas ^a   Foster, Steve J ^a   Maciewicz, Rose ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

BB 1101; ENZYME INHIBITOR; ETHER DERIVATIVE; HYDROXAMIC ACID; MARIMASTAT; METALLOPROTEINASE; PRINOMASTAT; SUCCINIC ACID; SULFIDE; SULFONAMIDE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CYTOKINE PRODUCTION; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME ASSAY; ENZYME INHIBITION; MARMOSET; NONHUMAN;

ADAM PROTEINS; ADMINISTRATION, ORAL; ANIMALS; CALLITHRIX; HUMANS; HYDROXAMIC ACIDS; METALLOENDOPEPTIDASES; PROTEASE INHIBITORS; QUINAZOLINES; SUCCINATES; TUMOR NECROSIS FACTOR-ALPHA;

EID: 0032727980     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm990377j     Document Type: Article

References (70)

1. (a) Woessner, J. F. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991, 5, 2145-2154.
2. (b) Birkedal-Hansen, H.; Morre, W. G. I.; Bodden, M. K.; Windsor, L. J.; Birkedal-Hansen, B.; De Carlo, A.; Engler J. A. Matrix metalloproteases: a review. Crit. Rev. Oral. Biol. Med. 1993, 4, 197-250.
3. (a) Brown, P. D. Matrix metalloproteinase inhibitors in the treatment of cancer. Med. Oncol. 1997, 14, 1-10.
4. (b) Zucker, S.; Lysik, R. M.; Zarrabi, H. M.; Moll, U.; Tickle, S. P.; Stetler-Stevenson, W.; Baker, T. S.; Docherty A. J. P. Plasma Assay of Matrix Metalloproteases (MMPs) and MMP-Inhibitor Complexes in Cancer. Ann. N.Y. Acad. Sci. 1994, 732, 248-262.
5. (a) Ahrens, D.; Koch, A. E.; Pope, R. M.; Steinpicarella, H.; Niedbala, M. J. Expression of Matrix Metalloproteinase (96-kd Gelatinase-B) in Human Rheumatoid Arthritis. Arthritis Rheum. 1896, 39, 1576-1587.
6. (b) Blasev, J.; Tuebel, S.; Haasjosthusmann, V.; Romisch, J.; Krahlmateblowski, V.; Freudenberg, W.; Fricke, R.; Tschesche, H. Determination of Metalloproteinases, Plasminogen-Activators and their Inhibitors in the Synovial Fluids of Patients with Rheumatoid Arthritis during Chemical Synoviorthesis. Clin. Chim. Acts 1996, 244, 17-33.
7. (c) Cawston, T. Metalloproteinase inhibitors and the prevention of connective tissue breakdown. Pharmacol. Ther. 1996, 70, 163-182.
8. (a) Beckett, R. P. Recent advances in the field of matrix metalloproteinase inhibitors. Exp. Opin. Ther. Patents 1996, 6, 1305-1315.
9. (b) Beckett, R. P.; Davidson, A. H.; Drummond, A. H.; Huxley, P.; Whittaker, M. Recent advances in matrix metalloproteinase inhibitor research. Drug Discovery Today 1998, 1, 16-26.
10. (c) Hagmann, W. K.; Lark, M. W.; Becker, J. W. Inhibition of matrix metalloproteinases. Ann. Rep. Med. Chem. 1996, 31, 231-240.
11. (d) Beckett, R. P.; Whittaker, M. Matrix metalloproteinase inhibitors 1998. Expert Opin. Ther. Pat. 1998, 8, 259-282.
12. Bemelmans, M. H. A.; van Tits, L. J. H.; Buurman, W. A. Tumor Necrosis Factor: Function, Release and Clearance. Crit. Rev. Immunol. 1996, 16, 1-11.
13. (a) Sekut, L.; Connolly, K. M. Pathophysiology and regulation of TNF-α in inflammation. Drug News Perspect. 1996, 9, 261-267.
14. (b) Rink, L.; Kirchner, H. Recent Progress in the Tumor Necrosis Factor-α Field. Int. Arch. Allergy Immunol. 1996, 111, 199-209.
15. (c) Brennan, F. M.; Maini, R. N.; Feldmann, M. TNFα - A pivotal role in rheumatoid arthritis? Br. J. Rheumatol. 1992, 31, 293-298.
16. (d) Maini, R. N.; Brennan, F. M.; Williams, R.; Chu, C. Q.; Cope, A. P.; Gibbons, D.; Elliot, M.; Feldmann, M. TNFα in rheumatoid arthritis and prospects of anti-TNF therapy. Clin. Exp. Rheumatol. 1993, 11 (supp. 8), S173-S175.
17. (a) Shire, M. G.; Muller, G. W. TNFα inhibitors and rheumatoid arthritis. Expert Opin. Ther. Pat. 1998, 8, 531-544.
18. (b) Eigler, A.; Sinka, B.; Hartmann, G.; Endres, S. Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol. Today 1997, 18, 487-492.
19. (c) Marriott, J. B.; Westby, M.; Dalgleish, A. G. Therapeutic potential of TNF-α inhibitors old and new. Drug Discovery Today 1997, 2, 273-282.
20. (d) Black, R. A.; Bird, T. A.; Mohler, K. M. Agents that block TNF-α synthesis or activity. Ann. Rep. Med. Chem. 1997, 32, 241-250.
21. (e) Camussi, G.; Lupia, E. The future role of anti-tumour necrosis factor (TNF) products in the treatment of rheumatoid arthritis. Drugs 1998, 55, 613-620.
22. (a) Moreland, L. W.; Baumgartner, S. W.; Schiff, M. H. et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Eng. J. Med. 1997, 337, 141-147.
23. (b) Cameron, A. Anti TNF-α treatments set to mop up in rheumatoid arthritis. InPharma 7 Feb. 1998, 1123, 9-10.
24. (a) Maini, R. N.; Elliott, M. J.; Brennan, F. M.; Feldmann, M. Beneficial effects of tumour necrosis factor-alpha blockade in rheumatoid arthritis. Clin. Exp. Immunol. 1995, 101, 207-212.
25. (b) Feldmann, M.; Brennan, F.; Palcolog, E.; Taylor, P.; Maini, R. N. Antitumor necrosis factor alpha therapy of rheumatoid arthritis. Mechanism of Action. Eur. Cytokine Network 1997, 8, 297-300.
26. (a) Georgopoulos, S.; Plows, D.; Kollias, G. Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J. Inflammation 1996, 46, 86-97.
27. (b) Solomon, K. A.; Covington, M. B.; DeCicco, C. P.; Newton, R. C. The fate of proTNFα following inhibition of metalloprotease dependent processing to soluble TNFα in human monocytes. J. Immunol 1997, 159, 4524.
28. (a) Black, R. A.; Rauch, C. T.; Korosky, C. J.; et al. A metalloproteinase disintegrin that releases tumour necrosis factor-α from cells. Nature 1997, 385, 729-733.
29. (b) Moss, M. L.; Jin, S.-L. C.; Milla, M. E.; et al. Cloning a disintegrin metalloproteinase that processes precursor tumor-necrosis factor-α. Nature 1997, 385, 733-736.
30. (a) Mohler, K. M.; Sleath, P. R.; Fitzner J. N.; et al. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 1994, 370, 218-220.
31. (b) McGeehan, G. M.; Becherer, J. D.; Bast, R. C.; et al. Regulation of tumour necrosis factor-α by a metalloproteinaae inhibitor. Nature 1994, 370, 558-561.
32. (c) Gearing, A. J. H.; Beckett, P.; Christodoulou, M.; et al. Processing of tumour necrosis factor-α precursor by metalloproteinases. Nature 1994, 370, 555-557.
33. DiMartino, M.; Wolff, C.; High, W.; Stroup, G.; Hoffman, S.; Laydon, J.; Lee, J. C.; Bertolini. D.; Galloway, W. A.; Crimmin, M. J.; Davis, M.; Davies, S. Antiarthritic activity of hydroxamic acid based pseudopeptide inhibitors of matrix metalloproteinases and TNFα processing. Inflammation Res. 1996, 46, 211-215.
34. Pratt, L. M.; Beckett, R. P.; Bellamy, C. L. et al. The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen Rearrangement. Bioorg. Med. Chem. Lett. 1998, 8, 1359-1364; α-cyclopentyl substitution increases in vivo properties at least in the rat.
35. Zook, S. E.; Dajnino, R.; Deason, M. E.; Bender, S. L.; Melnick, M. J. PCT Int. App. W097/20824 (Agouron).
36. (a) Singh, J.; Conzentino, P.; Cundy, K.; Gainor, J. A.; Gilliam, C. L.; Gordon, T. D.; Johnson, J. A.; Morgan, B. A.; Schneider, E. D.; Wahl, R. C.; Whipple, D. A. Relationship between structure and bioavailability in a series of hydroxamate-based metalloprotease inhibitors. Bioorg. Med. Chem. Lett. 1995, 5, 337-342.
37. (b) Broadhurst, M. J.; Brown, P. A.; Lawton, G.; Ballantyne, N.; Borkakoti, N.; Bottomley, K. M. K.; Cooper, M. I.; Eatherton, A. J.; Kilford, I. R.; Malsher, P. J.; Nixon, J. S.; Lewis, E. J.; Sutton, B. M.; Johnson, W. H. Design and synthesis of the cartilage protective agent (CPA, Ro32-35555). Bioorg. Med. Chem. Lett. 1991, 7, 2229.
38. Lippi, A.; Criscuoli, M.; Canali, S.; Sabissi, A. Reductive metabolism and its role in the disposition of the hydroxamic angiotensin-converting enzyme inhibitor idrapril calcuim in rat. Xenobiotica 1996, 26, 551-558.
39. Calculations were performed with the molecular modeling software package SYBYL 6.2 (Tripos Associates, St. Louis, MO) on a Silicon Graphics Indigo Elan workstation. MD simulations were performed with the Tripos force field with the electrostatic term at 600K, for 210000 ps with steps of 1 ps. The solvent effect was approximated by a distance dependent dielectric constant.
40. Beckett, R. P.; Crimmin, M. J.; Davis, M. H.; Spavold, Z. A short diastereoselective synthesis of 2,3-disubstituted succinates. Synlett 1993, 137-138.
41. As opposed to standard alkylations with alkyl halides which gave only the syn isomer (ref 19), reaction of the dianion of 7 with disulfides gave a mixture of syn and anti diastereoisomers, presumably due to partial formation of the sulfur stabilized anion followed by reprotonation.
42. Barlaam, B.; Hamon, A.; Maudet, M. New hydroxylamines for the synthesis of hydroxamic acids. Tetrahedron Lett. 1998, 39, 7865-7868.
43. 2 led a mixture of 2 and 12 due to epimerization of the arylthio substituent.
44. Structure assignment of anhydrides 13a and 14a was proven by NOE experiments: 13a showed a strong NOE effect (∼5%) between the 2 protons on the ring whereas 14a showed an NOE effect between the methylene of the isobutyl and the proton next to SPh.
45. The synthesis of intermediates 15 and 23 was published earlier in: Barlaam, B.; Koza, P.; Berriot, J. Solid phase synthesis of hydroxamic acid based TNFα convertase inhibitors. Tetrahedron 1999, 55, 7221-7232.
46. Levy, D. E.; Lapierre, F.; Liang, W.; Ye, W.; Lange, C. W.; Li, X.; Grobelny, D.; Casabonne, M.; Tyrell, D.; Holme, K.; Nadzan, A.; Galardy, R. E. Matrix Metalloproteinase Inhibitors: A Structure-Activity Study J. Med. Chem. 1998, 41, 199-236.
47. Gowraveram, M. R.; Tomczuk, B. E.; Crowravaram, M. R.; Johnson, J. S.; Delecki, M.; Cook, E. R.; Ghose, A. K.; Mathiowetz, A. M.; Spurlino, J. C.; Rubin, B.; Smith, D. L.; Pulvino, T.; Wahl, R. C. Inhibition of matrix metalloproteinases by hydroxamates containing novel P'1 heteroatom based modifications. J. Med. Chem. 1995, 38, 2570-2581.
48. Grams, F.; Crimmin, M.; Hinnes, L.; Huxley, P.; Pieper, M.; Tschesche, H.; Bode, W. Structure determination and analysis of human neutrophil collagenase complexed with a hydroxamate inhibitor. Biochemistry 1995, 34, 14012-14020.
49. Disubstitution alpha to the hydroxamic acid has been shown to maintain potency in a few rare cases: (a) Jacobson, I. C.; Reddy, P. G.; Wasserman, Z. R.; Hardman, K. D.; Covington, M. B.; Arner E. C.; Copeland, R. A.; Decicco, C. P.; Magolda, R. L. Structure-based design and synthesis of a series of hydroxamic acids with a quaternary-hydroxy group in P1 as inhibitors of matrix metalloproteinases. Bioorg. Med. Chem. Lett. 1998, 8, 837-842.
50. (b) Curtin, M. L.; Garland, .R. B.; Davidsen, S. K.; Marcotte, P. A.; Albert, D. H.; Magoc, T. J.; Hutchins, C. Broad spectrum matrix metalloproteinase inhibitors with P1 Cα gem-disubstitution. Bioorg. Med. Chem. Lett. 1998, 8, 1443.
51. Maskos, K.; Fernandez-Catalan, C.; Huber, R.; Bourenkov, G. P.; et al. Crystal structure of the catalytic domain of human tumor necrosis factor a converting enzyme. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3408-3412.
52. Serum protein binding was evaluated on selected compounds and was found low: 2a: 60% at 10 μM concentration in rat serum; 3a: 20% (same conditions). Unpublished results.
53. At the time of this study, the amino acid sequence of TACE was not known, but it was clear that this enzyme was close to the MMP family. Therefore, we based our initial structural approach of TACE on the crystal structure of collagenase (PDB entry 1MNC). Subsequently, it became evident that TACE was a new member of the mammalian Adamalysin family (or ADAMs), which presents a good level of sequence homology with the snake venom metalloproteinase family (SVMPs). We built a homology model of TACE starting from the available X-ray structures of two closely related SVMPs, Adamalysin and Atrolysin-c (PDB entry codes 1IAG and 1HTC). Whereas many inclusions left our model imprecise, the high level of sequence similarity within the active site itself enabled us to use this model for the design of small, nonselective, inhibitory molecules. The recent publication of the X-ray structure of TACE (ref 29) confirmed the high structural similarity between the MMPs, the SVMPs, and ADAMs in the vicinity of the zinc binding site.
54. Scrip on line, 1 July 1998, S00586508F, "Bayer and Agouron compete in MMP (matrix metalloproteinase) inhibitors field."
55. Bird, T. G. C.; Barlaam, B. C.; Lambert, C. M. P. Preparation of sulfur-containing aminoacyl hydroxamic acid derivatives as tumor necrosis factor and matrix metalloprotease inhibitors. PCT Int. App. WO97/42168 (Zeneca). Chem. Abstr. 127: 359105.
56. Gearing, A. J. H.; Beckett, P.; Christodoulou, M.; Churchill, M. et al. Matrix metalloproteinases and processing of pro-TNF-α J. Leukocyte Biol. 1895, 57, 774-777.
57. Knight, C. G.; Willenbrock, F.; Murphy, G. A novel coumarin-labeled peptide for sensitive continuous assays of the matrix metalloproteinases. FEBS Lett. 1992, 296, 263-266.
58. Desch, C. E.; Kovach, N. L.; Present, W.; Boyles, C.; Harlan, J. M. Production of Human Tumor Necrosis Factor from Whole Blood ex Vivo. Lymphokine Res. 1989, 8, 141-146.
59. Bird, T. G. C. Preparation of 4-[5-(heteroarylthio)-2-thienyl]-4-methoxytetrahydropyrans and analogues as 5-lipoxygenase inhibitors. Eur. Pat. Appl. EP 462812 (ICI); Chem. Abstr. 116, 214346.
60. Krishnamurthy, S.; Aimino, D. Rapid and selective reduction of functionalized aromatic disulfides with lithium tri-tert-butoxyaluminohydride. A remarkable steric and electronic control. Comparison of various hydride reagents. J. Org. Chem. 1989, 54, 4458-4462.
61. Bordwell, F. G.; Anderson, H. M. Conjugation of methylsulfonyl and nitro groups with the mercapto group in thiophenols. J. Am. Chem. Soc. 1953, 75, 6019-6022.
62. Prepared from 8-mercaptomethylquinoline (Bankovskis, J.; Misulovina, Z.; Ievins, A.; Buka, M. The reaction of 8-(methylthio)-quinoline with metal ions. Chem. Abstr. 1961, 55, 14458h).
63. 5.
64. Prepared from 4-pyridineethylsulfonic acid (Romero, D. L.; Thomas, R. C. Preparation of substituted indoles as anti-AIDS pharmaceuticals. PCT Int. App. W093/01181 (Upjohn)).
65. Bird, T. G. C.; Olivier, A. Inhibitors of leukotriene B4. Synthesis and SAR of new β-enaminoester open-chain analogues of Zeneca ZD2138. Bioorg. Med. Chem. Lett. 1996, 6, 515-520.
66. Crawley, G. C.; Edwards, P. N.; Girodeau, J. M. Preparation of (heterocyclylmethoxyphenyl) tetrahydropyrans and related compounds as lipoxygenase inhibitors. European Patent Application EP 385662.
67. Hughes, L. R.; Jackman, A. L.; Oldfield, J.; Smith, R. C.; Burrows, K. D.; Marsham, P. R.; Bishop, J. A. M.; Jones, T. R.; O'Conner, B. M.; Calvert, A. H. Quinazoline Antifolate Thymidylate Synthase Inhibitors: Alkyl, Substituted Alkyl, and Aryl Substituents in the C2 Position. J. Med. Chem. 1990, 33, 3060-3067.
68. 7-Bromo-6-bromomethyl-2-methyl-4-oxo-3,4-dihydroquinazoline was prepared by standard deprotection (aqueous HCl) of (7-bromo-6-bromomethyl-2-methyl-4-oxo-3,4-dihydroquinazolin-3-yl)methyl 2,2-dimethylpropanoate [Pegg, S. J.; Wardleworth, J. M. Preparation of antitumor quinazoline derivatives. UK Patent Application GB 2264946].
69. Maeda, T.; Takae, M.; Ishibashi, A.; Ariyoshi, T.; Yokoo, M. Preparation of (heteroalkyl)(phenylalkyl) amines and fungicides containing them. Japan Patent JP 02223558.
70. Hiraiwa, T.; Takeda, K.; Nakano, J.; Sudani, M.; Furuhata, K.; Takata, M.; Kawafuchi, H.; Watanabe, I. N-Aryl-N′-allylpiperazines as cerebral vasodilators. Ger. Offen. DE 3906920.