Anionic- and lipophilic-mediated surface binding inhibitors of human leukocyte elastase

Journal of Medicinal Chemistry

Volumn 40, Issue 21, 1997, Pages 3408-3422

  Regan, John ^a  

^a Departments of Medicinal Chemistry and Inflammation Biology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

[4 (4 BROMOPHENYLSULFONYLCARBAMOYL)BENZOYL]VALYLPROLINE N (2 METHYL 1 TRIFLUOROACETYLPROPYL)AMIDE; CATHEPSIN G; ELASTASE INHIBITOR; LEUKOCYTE ELASTASE; OLIGOMER; PHENOXYACETIC ACID DERIVATIVE; RG 13577; THROMBIN; UNCLASSIFIED DRUG;

ARTICLE; CONTROLLED STUDY; DRUG MECHANISM; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME SPECIFICITY; ENZYME SUBSTRATE COMPLEX; HUMAN; INHIBITION KINETICS; LEUKOCYTE; LIPOPHILICITY;

BENZHYDRYL COMPOUNDS; BINDING SITES; BINDING, COMPETITIVE; BLOOD PROTEINS; CATHEPSINS; ENZYME INHIBITORS; HUMANS; KINETICS; LEUKOCYTE ELASTASE; MOLECULAR STRUCTURE; OLIGOPEPTIDES; PHENOXYACETATES; PYRROLIDONECARBOXYLIC ACID; SERINE ENDOPEPTIDASES; THROMBIN;

EID: 9844233707     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970251r     Document Type: Article

References (71)

1. Ohlsson, K.; Olsson, I. The Neutral Proteases of Human Granulocytes: Isolation and Partial Characterization of Granulocyte Elastase. Eur. J. Biochem. 1974, 42, 519-527.
2. Weissman, G.; Smolen, J. E.; Korchak, H. M. Release of Inflammatory Mediators From Stimulated Neutrophils. N. Engl, J. Med. 1980, 33 2, 7-34.
3. Starkcy, P. M.; Barrett, A. J. Human Lysosomal Elastase: Catalytic and Inmunological Properties. Biochem J. 1976, 755, 265-271.
4. Sanhaus, R. A. Elastase May Play a Central Role in Neutrophil Migration Through Connective Tissues. In Pulmonary Emphysema and Proteolysis; Taylor, J. C., Mittman, C., Eds.; Academy Press: New York, 1987; pp 227-233.
5. Travis, J. Neutrophils, Lymphocytes and Lungs. In Pathophysiology of Pulmonary Cells. Neutrophils and Lymphocytes; Baggiolini, M., Pozzi, E., Semenzato, G., Eds.; Masson Press: Milan, 1990; pp 65-76.
6. Travis, J.; Salvesen, G. S. Human Plasma Proteinase Inhibitors. Anna. Rev. Biochem. 1983, 52, 655-709.
7. Thompson, R. C.; Ohlsson, K. Isolation Properties and Complete Amino Acid Sequence of Human Secretory Leukocyte Proteinase Inhibitors, a Potent Inhibitor of Leukocyte Elastase. Proc. Natl. Acad. Sei. U.SA. 1986, 83, 6692-6696.
8. See: Pulmonary Emphysema: The Rationale for Therapeutic Intervention. Weinbaum, G., Giles, R. E., Krell, R. D., Eds. Ann. N.Y. Acad. Sei. 1991, 624.
9. Merritt, T. A.; Cochrane, C. G.; Holcomb, K.; Bohl, B.; Hallman, M.; Strayer, D.; Edwards, D.; Gluck, L., Elastase and ajProteinase Inhibitor Activity in Trachea! Aspirates During Respiratory Distress Syndrome. J. Clin. Invest. 1983, 72, 656-666.
10. Suter, S.; Schaad, L.; Roux, L.; Nydegger, V. E.; Walduogel, F. A. Granulocyte Neutral Proteases and Psuedomonas Elastase as Possible Causes of Airway Damage in Patients with Cystic Fibrosis. J. Infect. Dis. 1984, 149, 523-531.
11. 1-antitrypsin and ai-antichymotrypsin by Neutrophils in Arthritic Joints. Arthritis Rheum. 1993, 36, 168-180.
12. Reviews: (a) Groutas, W. C. Inhibitors of Leukocyte Elastase and Leukocyte Cathepsin G. Agents for the Treatment of Emphysema and Related Ailments. Med. Res. Rev. 1987, 7,227-241.
13. (b) Trainor, D. A. Synthetic Inhibitors of Human Neutrophil Elastase. Trends Pharmacol. Sei. 1987, 8, 303-307.
14. Bernstein, P. R.; Edwards, P. D.; Williams, J. C. Inhibitors of Human Leukocyte Elastase. Prog. Med. Chem. 1994, 31, 60-120.
15. Edwards, P. D.; Bernstein, P. R. Synthetic Inhibitors of Elastase. Med. Res. Reu. 1994, 14, 127-194.
16. Doherty, N. S.; Dinerstein, R. J.; Mehdi, S. Novel Inhibitors of Polymorphonuclear Neutrophil Elastase and Cathepsin G.: Evaluation in Vitro of Their Potential for the Treatment of Inflammatory Connective Tissue Damage. Int. J. Immunopharm. 1990, 12, 785-795.
17. Williams, J. C.; Falcone, R. C.; Knee, C.; Stein, R. L.; Strimpler, A. M.; Reaves, B. Biological Characterization of ICI 200, 880 and ICI 200, 355, Novel Inhibitors of Human Neutrophil Elastase. Am. Rev. Respir. Dis. 1991, 144, 875-883.
18. (a) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Barley, R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Tuthill, R. A.; Warner, P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 1259-1261.
19. (b) Edwards, P. D.; Ändisik, D. W.; Strimpler, A. M.: Gomes, B.; Tuthill, R. A. Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethly Ketones. J. Med. Chem. 1996,39, 1112-1124 and refs 34, 35, 36, and 37 of this paper for other analogs,
20. Skiles, J. W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger, K. G.; Mauldin, S. C.; Vitous, J.; Mui, P. W.; Jacober, S.; Chow, G.; Matteo, M.; Skoog, M.; Weldon, S. M.; Possanza, G.; Keirns, J.; Letts, G.; Rosenthal, A. S. Inhibition of Human Leukocyte Elastase by N-Substituted Peptidyl Trifiuoromethyl Ketones. J. Med. Chem. 1992, 35, 641-662.
21. Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burckhart, J. P.; Chen, T.-M.; Durham, S. L.; Hare, C. M.; Huber, E. W.; Janusz, M. J.; Koehl, J. R.; Marquart, A. L.; Mehdi, S.; Peet, N. P. Inhibition of Human Neutrophil Elastase with Peptidyl Electrophilic Ketones. 2. Orally Active Pc-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554.
22. (a) Edwards, P. D.; Meyer, E. F., Jr.; Vijayalakshmi, J.; Tuthill, P.; Andisik, D. A.; Gomes, B.; Strimpler, A. Design, Synthesis and Kinetic Evaluation of a Unique Class of Elastase Inhibitors, the Peptidyl a-Keto-benzoxazoles, and the X-ray Crystal Structure of the Covalent Complex between Porcine Pancreatic Elastase and Ac-Ala-Pro-Val-2-Benzoxazole. J. Am. Chem. Soc. 1992,114,1854-1863.
23. (b) Edwards, P. D. Zottola, M. A.; Davis, M.; Williams, J.; Tuthill, P. A. Peptidyl a-Ketoheterocyclic Inhibitors of HumanNeutrophil Elastase. 3. In Vitro and in Vivo Potency of a Series of Peptidyl α-Ketobenzoxazoles. J. Med. Chem. 1995, 38, 3972-3982.
24. Kennedy, A. J.; Cline, A.; Ney, U. M.; Johnson, W. H.; Roberts, N. A. The Effect of a Peptidyl Aldehyde Reversible Inhibitor of Elastase on a Human Leukocyte Elastase-Induced Model of Emphysema in the Hamster. Eur. J. Respir. Dis. 1987, 71, 472-478.
25. Kettner, C. A.; Shenri, A. B. Inhibtion of the Serine Proteases Leukocyte Elastase, Pancreatic Elastase, Cathepsin G and Chymotrypsin by Peptide Boronic Acids. J. Biol. Chem. 1984, 259, 15106-15114.
26. Hori, H.; Yasutake, A.; Minematsu, Y.; Powers, J. C. Inhibition of Human Leukocyte Elastase, Porcine Pancreatic Elastase and Cathepsin G by Peptide Ketones. In Peptides, Structure and Function. Proceeding of the Ninth American Peptide Symposium; Deber, C. M., Hruby, V. J., Kopple, D. K., Eds.; Pierce Chemical Co.: Rockford, IL, 1985; pp 819-822.
27. (a) Takahashi, L. H.; Radhakrishman, R.; Rosenfield, R. E., Jr.; Meyer, E. F., Jr.; Trainor, D. A. Crystal Structures of the Covalent Complex Formed by a Peptidyl α,α-Difluoro-β-Keto Amide with Porcine Pancreatic Elastase at 1.78-A Resolution. J. Am. Chem. Soc. 1989, 111, 3368-3374.
28. (b) Bernstein, P. R.; Kosmider, B. J.; Vacek, E. P.; Veale, C. A.; Gomes, B. C. Examination of Peptidic α,β-diamino a,a-difluorketones as Inhibitors of Human Leukocyte Elastase. Bioorg. Med. Chem. Lett. 1994, 4, 2175-2178.
29. (a) Finke, P. E.; Shah, S. K.; Ashe, B. M.; Ball, R. G.; Blacklock, T. J.; Bonney, R. J.; Brause, K. A.; Chandler, G. O.; Cotton, M.; Davies, P.; Dellea, P. S.; Dorn, C. P., Jr.; Fletcher, D. S.; O'Grady, L. A.; Hagmann, W. K.; Hand, K. M.; Knight, W. B.; Maycock, A. L.; Mumford, R. A.; Osigna, D. G.; Sohar, P.; Thompson, K. R.; Weston, H.; Doherty, J. B. Inhibition of Human Leukocyte Elastase. 4. Selection of a Substituted Cephalosporin (L-658, 758) as a Topical Aerosol. J. Med. Chem. 1992, 35, 3731-3744.
30. (b) Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hand, K M.; Maycock, A. L.; Osigna, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. Orally Acive /î-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and StructureActivity Relationships for 3,3-Dialkylazetidin-2-ones. J. Med. Chem. 1995, 38, 2449-2462.
31. Durette, P. L.; Chabin, R. M.; Fletcher, D. S.; Green, B. G.; Hanlon, W. A.; Humes, J. L.; Knight, W. B.; Lanza, T. J.; Mumford, R. A.; Pacholok, S.; MacCoss, M. Phosporous Acid Analogs of L-680-833, a Potent Monocyclic β-Lactam Inhibitor of Human Leukocyte Elastase. Bioorg. Med. Chem. Lett. 1995, 5, 271-274.
32. Jasys, V. J.; Kellogg, M. S.; Volkmann, R. A. Synthesis of Novel SulfenamideContaining β-Lactams Tetrahedron Lett. 1991,32, 3771-3774.
33. Groutas, W. C.; Chong, L. S.; Epp, J. B.; Venkataraman, R.; Brubaker, M. J.; Stanga, M. A.; Kirn, E.-H.; Keller, C. E. Inhibition of Human Leukocyte Elastase and Cathepsin G by Isoxazline Derivatives. Bioorg. Med. Chem. Lett. 1992,2,15711574.
34. Groutas, W. C.; Epp, J. B.; Venkataraman, R.; Kuang, R.; Truong, T. M.; McClenahan, J. J.; Prakash, O. Design, Synthesis, and In Vitro Inhibitory Activity Toward Human Leukocyte Elastase, Cathepsin G, and Proteinase 3 of Saccharin-Derived Sulfones and Congeners. Bioorg. Med. Chem. Lett. 1996, 4, 1393-1400.
35. (a) Subramanyam, C.; Bell, M. R.; Carabateas, P.; Court, J. J.; Dority, J. A., Jr.; Ferguson, E.; Gordon, R.; Hlasta, D. J.; Kumar, V.; Saindane, M. 2,6-Disubstituted Aryl Carboxylic Acids, Leaving Groups "Par Excellence" for Benzisothiazolone Inhibitors of Human Leukocyte Elastase. J. Med. Chem. 1994, 37, 26232626.
36. (b) Subramanyam, C.; Bell, M. R.; Chose, A. K.; Kumar, V.; Dunlap, R. P.; Franke, C.; Mura, A. J. Inhibitors of Human Leukocyte Elastase. 3. Inhibition by Tetrahydrobenzisothiazolinylmethyl Aryl Carboxylates. Bioorg. Med. Chem. Lett. 1995,5, 325-330.
37. Subramanyam, C.; Bell, M. R.; Ferguson, E.; Gordon, R. G.; Dunlap, R. P.; Franke, C.; Mura, A. J. Inhibitors of Human Leukocyte Elastase. 2. Synthesis and SAR of Benzisothiazolinylmethy Aryl Ethers. Bioorg. Med. Chem. Lett. 1995, 5, 319-324.
38. Hlasta, D. J.; Bell, M. R.; Court, J. J.; Cundy, K. C.; Desai, R. C.; Ferguson, E. W.; Gordon, R. C.; Kumar, V.; Maycock, A. L.; Subramanyam, C. The Design of Potent and . Stable Benzisothiazolone Inhibitors of human Leukocyte Elastase. Bioorg. Med. Chem. Lett. 1995, 5, 331-337.
39. Cunningham, R. T.; Mangold, S. E.; Spruce, L. W.; Ying, Q. L.; Simon, S. R.; Wieczorek, M.; Ross, S.; Cheronis, J. C.; Kirschenheuter, G. P. Synthesis and Evaluation of CE-0266: A New Human Neutrophil Elastase Inhibitor. Bioorg. Chem. 1992,20, 345-355.
40. Simon, S.; Vered, M.; Rinehart, A.; Janoff, A. Inhibition of Human Neutrophil Elastase by Polyguanylic Acid and Other Synthetic RNA Homopolymers. Exp. Lung Res. 1988, 14, 8599.
41. Tyagi, S. C.; Simon, S. R. Interaction of Neutrophil Elastase with Hydrophobie Polyanionic Chelators. Biochem. Cell Biol. 1991, 69, 624-629.
42. (a) Redini, F.; Tixier, J.-M.; Petitou, M.; Choay, J.; Robert, L.; Hornback, W. Inhibition of Leukocyte Elastase by Heparin and its Derivatives. Biochem. J. 1988,252, 515-519.
43. 1-Proteinase Inhibitor. Biochem. Pharmacol. 1988, 37, 42574261.
44. Baici, A.; Salgam, P.; Ferh, K.; Boni, A. Inhibition of Human Polymophonuclear Leukocytes by a Glycosminoglycan Polysulphate (Arteparon). Biochem. Pharmacol. 1980,29,17231728.
45. Baici, A.; Bradamante, P.; Interactions Between Human Leukocyte Elastase and Chondroitin Sulfate. Chem. Biol. Interact. 1984, 51, 1-11.
46. Rypacek, F.; Banks, W. R.; Noskova, D.; Digenis, G. A. Synthetic Inhibitors of Human Leukocyte Elastase. 1. Synthesis of Peptidyl Carbamates Bound to Water-Soluble Polymers: Poly-α,β-[N-(2-hydroxyethyl)-D,L-aspartamide] and Poly-a-[N5-(2-hydroxyethyl)-L-glutamine]. J. Med. Chem. 1994, 37, 1850-1856.
47. Kawabata, K.; Suzuki, M.; Sugitani, M.; Imaki, K.; Toda, M.; Miyamoto, T. ONO-5046, a Novel Inhibitor of Human Neutrophil Elastase. Biochem. Biophys. Res. Comm. 1991, 777, 814-820. "
48. Kerrigan, J. E.; Oleksyszyn, J.; Kam, C.-M.; Selzer, J.; Powers, J. C. Mechanism-Based Isocoumarin Inhibitors for Human Leukocyte Elastase. Effect of the 7-Amino Substituent and 3-Alkoxy Group in 3-Alkoxy-7-amino-4-chloroisocoumarins on Inhibitory Potency. J. Med. Chem. 1995, 38, 544-552.
49. Janusz, M. J.; Hare, M. Inhibition of Human Neutrophil Elastase and Cathepsin G by a Biphenyl Disulfonic Acid Copolymer. Int. J. Immunopharm. 1994, 16, 623-632.
50. (a) Regan, J. R.; Bruno, J. G.; Chang, M. N.; Sabatino, R.; D'Alisa, R.; Ben-Sasson, S. A.; Eilat, D. Mimicry of Biological Macromolecules by Polyaromatic Anionic Compounds. J. Bioact. Compt. Polymers 1993, 8, 317-337.
51. (b) Benezra, M.; Vlodavsky, I.; Yayon, A.; Bas-Shavit, R.; Regan, J. Chang, M.; Ben-Sasson, S. Reversal of Basic Fibroblast Growth Factor-Mediated Autocrine Cell Transformation by Aromatic Anionic Compounds. Cancer Res. 1992, 52, 5656-5662.
52. Benezra, M.; Ben-Sasson, S. A.; Regan, J.; Chang, M.; Bar-Shavit, R.; Vlodavsky, I. Antiproliferative Activity to Vascular Smooth Muscle Cells and Receptor Binding of Heparin-Mimicking Polyaromatic Anionic Compounds. Arteriosclerosis Thromb. 1994, 14, 1992-1994.
53. Ben-Sasson, S. A.; Newman, J. Unpublished results.
54. Bruno, J. G.; Chang, M. N.; Choi-Sledeski, Y. M.; Green, D. M.; McGarry, D. G.; Regan, J. R.;Volz, F. A. Synthesis of Functonalized Aromatic Oligomers From a Versatile Diphenylmethane Template. J. Org. Chem. 1997, 62, 5174-5190.
55. An analogous strategy has been reported for the identification of small anti-HIV compounds fom polymeric sources: Cushman, M.; Kanamathareddy, S. Synthesis of the Covalent Hydrate of the Incorrectly Assumed Structure of Aurintricarboxylic Acid (ATA). Tetrahedron 1990, 46, 1491-1498.
56. Cushman, M.; Kanamathareddy, S.; De Clerq, E.; Schols, D.; Goldman, M. E.; Bowen, J. A. Synthesis and Anti-HIV Activities of Low Molecular Weight Aurintricarboxylic Acid Fragments and Related Compounds. J. Med. Chem. 1991,34, 337-342.
57. Wang, P.; Kozlowski, J.; Cushman, M. Isolation and Structure Elucidation of Low Molecular Weight Components of Aurintricarboxylic Acid (ATA). J. Org. Chem. 1992, 57, 3861-3866.
58. Cushman, M.; Sherman, P. Inhibition of HIV-1 Integration Protein by Aurintricarboxylic Acid Monomers, Monomer Analogs and Polymer Fractions. Blochem. Biophys. Res. Commun. 1992, 185, 85-90.
59. Bode, W.; Meyer, E., Jr.; Powers, J. C. Human Leukocyte and Porcine Pancreatic Elastase: X-Ray Crystal Structures, Mechanism, Substrate Specificity and Mechanism-Based Inhibitors. Biochemistry 1989, 28, 1951-1963.
60. For a recent example of a conceptually similiar approach to enzyme inhibition, see: Jain, A.; Whitesides, G. M.; Alexander, R. S.; Christianson, D. W. Identification of Two Hydrophobie Patches in the Active-Site Cavity of Human Carbonic Anhydrase II by Solution-Phase and Solid-State Studies and Their Use in the Development of Tight-Binding Inhibitors. J. Med. Chem. 1994, 37, 2100-2105.
61. For the inhibition of HIV proteases by alkylation of solventexposed-cysteine residues near the active site see De Voss, J. J.; Sui, Z.; DeCamp, D. L.; Salto, R.; Babe L. M.; Craik, C. S.; Ortiz de Montellano, P. R. Haloperidol-Based Inhibitors of the HIV-1 and HIV-2 Proteases. J. Med. Chem. 1994,37, 665-673.
62. Review: Merkushev, E. B. Advances in the Synthesis of Iodoaromatic Compounds. Synthesis 1988, 923-937.
63. Berk, S. C.; Knöchel, P.; Yeh, M. C. P. General Approach to Highly Functionalized Benzylic Organometallics of Zinc and Copper. J. Org. Chem. 1988, 53, 5789-5791.
64. Wessel, H. P.; Tschopp, T. B.; Hosang, M.; Iberg, N. Identification of a Sulfated Tetrasaccharide with Heparin-Like Antiproliferative Activity. Bioorg. Med. Chem. Lett. 1994, 4, 1419-1422.
65. Weinstein, M.; Vosburgh, E.; Phillips, M.; Turner, N.; ChuteRose, L.; Moake, J. Isolation From Commercial Aurintricarboxylic Acid of the Most Effective Polymeric Inhibitors of von Willebrand Factor Interaction with Platelet Glycoprotein Ib. Comparison with Other Polyanionic and Polyaromatic Polymers. Blood 1991, 78, 2291-2298.
66. For the preparation of this calix[4]arene analog, see: Arduni A.; Pochini, A.; Reverberi, S.; Ungaro, R. p-t-Butyl-calix[4]arene Tetracarboxylic Acid. A Water Soluble Calixarene in a Cone Structure. J. Chem. Soc., Chem. Commun. 1984, 981-982.
67. Paliwal, S.; Greib, S.; Wilcox, C. S. Molecular Torsion Balance for Weak Molecular Recognition Forces. Effects of "Tilted-T Edge-to-Face Aromatic Interactions on Conformational Selection and Solid-State Structure. J. Am. Chem. Soc. 1994,116, 44974498.
68. For a recent discussion of this principle, see: Eaton, B. E.; Gold, L.; Zichi, D. A. Let's Get Specific: the Relationship Between Specificity and Affinity. Chem. Biol. 1995, 2, 633-638.
69. Conformational differences of the scaffolds resulting from the different anionic and lipophilic groups of 6 and 7a-f cannot, at this juncture, be excluded as additional factors governing biological potency.
70. Oison, T. A.; Sonder, S. A.; Wilner, G. D.; Fenton, J. W. II. Heparin Binding in Proximity to the Catalytic Site of Human a-Thrombin. Ann. N.Y. Acad. Sei. 1986, 485, 96-103.
71. Several different orientations of individual oligomers with HLE appear plausible (J. Barton, D. Cheney, private communication). We do not wish to promote one specific proposal for the entire class; rather the individual oligomers may interact in a separate fashion consistent with the general principle expressed.