Nonpeptidic inhibitors of human neutrophil elastase. 7. Design, synthesis, and in vitro activity of a series of pyridopyrimidine trifluoromethyl ketones

Journal of Medicinal Chemistry

Volumn 39, Issue 5, 1996, Pages 1112-1124

  Edwards, Philip D ^a   Andisik, Donald W ^a   Strimpler, Anne M ^a   Gomes, Bruce ^a   Tuthill, Paul A ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ELASTASE INHIBITOR; KETONE DERIVATIVE; LEUKOCYTE ELASTASE; PANCREATIC ELASTASE; PYRIDO[3,4 D]PYRIMIDINE TRIFLUOROMETHYL KETONE; UNCLASSIFIED DRUG;

ADULT RESPIRATORY DISTRESS SYNDROME; ARTICLE; ATHEROSCLEROSIS; CRYSTAL STRUCTURE; CYSTIC FIBROSIS; DRUG DESIGN; DRUG SYNTHESIS; INFLAMMATORY DISEASE; LUNG EMPHYSEMA; RHEUMATOID ARTHRITIS; STRUCTURE ACTIVITY RELATION;

AMINO ACID SEQUENCE; BINDING SITES; CHEMISTRY, PHYSICAL; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; KETONES; LEUKOCYTE ELASTASE; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MOLECULAR STRUCTURE; PANCREATIC ELASTASE; PYRIDINES; PYRIMIDINES; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030009748     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm950684z     Document Type: Article

References (41)

1. Abbreviations: HNE, human neutrophil elastase; PPE, porcine pancreatic elastase; Ac, acetyl; Cbz, benzyloxycarbonyl; TFMK, trifluoromethyl ketone; CAN, ceric ammonium nitrate; TEA, triethylamine; THF, tetrahydrofuran; DMSO, dimethyl sulfoxide; EDAC, 1-ethyl-[3-[3-(dimethylamino)propyl]]carbodiimide hydrochloride; HOBt, 1-hydroxybenzotriazole monohydrate; TBAF, tetra-n-butylammonium fluoride; TFA, trifluoroacetic acid; DMF, dimethylformamide; NMM, N-methylmorpholine; DMP, Dess-Martin periodinane, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; MeO, methoxy; Suc, succinyl; pNa, p-nitroanilide; PBS, phosphate-buffered saline; it, intratracheal; DPPA, diphenyl phosphorazidate.
2. For a comprehensive review of synthetic HNE inhibitors, see: Edwards, P. D.; Bernstein, P. R. Synthetic Inhibitors of Elastase. Med. Res. Rev. 1994, 14, 127-194.
3. Bieth, J. G. Elastases: Catalytic and Biological Properties. In Regulation of Matrix Accumulation; Mecham, R. P., Ed.; Academic Press: New York, 1986; pp 217-320.
4. Pulmonary Emphysema and Proteolysis: 1986; Taylor, J. C., Mittman, C., Eds.; Academic Press, Inc.: New York, 1987; pp 1-550.
5. Burchardi, H.; Stokke, T.; Hensel, I.; Köestering, H.; Rahlf, G.; Schlag, G.; Heine, H.; Horl, W. H. Adult Respiratory Distress Syndrome (ARDS): Experimental Models with Elastase and Thrombin Infusion in Pigs. Adv. Exp. Med. Biol. 1984, 167, 319-333.
6. Janoff, A. Granulocyte Elastase: Role in Arthritis and in Pulmonary Emphysema. In Neutral Proteases of Human Polymorphonuclear Leukocytes; Havermann, K., Janoff, A., Eds.; Urban and Schwarzenberg, Inc.: Baltimore, MD, 1978; pp 390-417.
7. Janoff, A. Elastase in Tissue Injury. Annu. Rev. Med. 1985, 36, 207-216.
8. Nadel, J. A. Role of Mast Cell and Neutrophil Proteases in Airway Secretion. Am. Rev. Respir. Dis. 1991, 144, S48-S51.
9. Stein, R. L.; Trainor, D. A.; Wildonger, R. A. Neutrophil Elastase. Annu. Rep. Med. Chem. 1985, 20, 237-246.
10. 1-Antitrypsin Deficiency. Scand. J. Clin. Lab. Invest. 1963, 15, 132-140.
11. 1-Antitrypsin Deficiency. Acta Med. Scand. 1965, 177 (Suppl. 432), 1-85.
12. Bernstein, P. R.; Edwards, P. D.; Williams, J. C. Inhibitors of Human Leukocyte Elastase. Prog. Med. Chem. 1994, 31, 59-120.
13. Williams, J. C.; Falcone, R. C.; Knee, C.; Stein, R. L.; Strimpler, A. M.; Reaves, B.; Giles, R. E.; Krell, R. D. Biologic Characterization of ICI 200,880 and ICI 200,355, Novel Inhibitors of Human Neutrophil Elastase. Am. Rev. Respir. Dis. 1991, 144, 875-883.
14. Sommerhoff, C. P.; Krell, R. D.; Williams, J. L.; Gomes, B. C.; Strimpler, A. M.; Nadel, J. A. Inhibition of Human Neutrophil Elastase by ICI 200,355. Eur. J. Pharm. 1991, 193, 153-158.
15. 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 (HLE) by N-substituted Peptidyl Trifluoromethyl Ketones. J. Med. Chem. 1992, 35, 641-662.
16. Edwards, P. D.; Zottola, M. A.; Davis, M.; Williams, J.; Tuthill, P. A. Peptidyl α-Ketoheterocyclic Inhibitors of Human Neutrophil Elastase. 3. In Vitro and in Vivo Potency of a Series of Peptidyl α-Ketobenzoxazoles. J. Med. Chem. 1995, 38, 3972-3982.
17. Soskel, N. T.; Watanabe, S.; Hardie, R.; Shenvi, A. B.; Punt, J. A.; Kettner, C. Effects of Dosage and Timing of Administration of a Peptide Boronic Acid Inhibitor on Lung Mechanics and Morphometrics in Elastase-Induced Emphysema in Hamsters. Am. Rev. Respir. Dis. 1986, 133, 635-638.
18. Soskel, N. T.; Watanabe, S.; Hardie, R.; Shenvi, A. B.; Punt, J. A.; Kettner, C. A New Peptide Boronic Acid Inhibitor of Elastase-Induced Lung Injury in Hamsters. Am. Rev. Respir. Dis. 1986, 133, 639-642.
19. Stone, P. J.; Lucey, E. C.; Snider, G. L. Induction and Exacerbation of Emphysema in Hamsters with Human Neutrophil Elastase Inactivated Reversibly by a Peptide Boronic Acid. Am. Rev. Respir. Dis. 1990, 141, 47-52.
20. Bonney, R. J.; Ashe, B.; Maycoek, A.; Dellea, P.; Hand, K.; Osinga, D.; Fletcher, D.; Mumford, R.; Davies, P.; Frankenfield, D.; Nolan, T.; Schaeffer, L.; Hagmann, W.; Finke, P.; Shah, S.; Dorn, C.; Doherty, J. Pharmacological Profile of the Substituted Beta-Lactam L-569,286: A Member of a New Class of Human PMN Elastase Inhibitors. J. Cell. Biochem. 1989, 39, 47-53.
21. Hagmann, W. K.; Shah, S. K.; Dorn, C. P.; O'Grady, L. A.; Hale, J. J.; Finke, P. E.; Thompson, K. R.; Brause, K. A.; Ashe, B. M.; Weston, H.; Dahlgren, M. E.; Maycoek, A. L.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Bonney, R. J.; Davies, P.; Fletcher, D. S.; Doherty, J. B. Prevention of Human Leukocyte Elastase-Mediated Lung Damage by 3-Alkyl-4-Azetidinones. Bioorg. Med. Chem. Lett. 1991, 1, 545-550.
22. 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.; Munford, R. A.; Osinga, 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.
23. Bergeson, S. H.; Edwards, P. D.; Krell; R. D.; Shaw, A.; Stein, R. L.; Stein, M. M.; Strimpler, A. M.; Trainor, D. A.; Wildonger, R. A.; Wolanin, D. J. Inhibition of Human Leukocyte Elastase By Peptide Trifluoromethyl Ketones. In Abstracts of Papers 193rd National Meeting of the American Chemical Society, Denver, CO, April 5-10, 1987; American Chemical Society: Washington, D. C., 1987; abstract number MEDI 0001.
24. Stein, R. L.; Strimpler, A. M.; Edwards, P. D.; Lewis, J. J.; Mauger, R. C.; Schwartz, J. A.; Stein, M. M., Trainor, D. A.; Wildonger, R. A.; Zottola, M. A. Mechanism of Slow-Binding Inhibition of Human Leukocyte Elastase by Trifluoromethyl Ketones. Biochemistry 1987, 26, 2682-2689.
25. Stein, M. M.; Wildonger, R. A.; Trainor, D. A.; Edwards, P. D.; Yee, Y. K.; Lewis, J. J.; Zottola, M. A.; Williams, J. C.; Strimpler, A. M. In Vitro and In Vivo Inhibition of Human Leukocyte Elastase (HLE) by Two Series of Electrophilic Carbonyl Containing Peptides. In Peptides: Chemistry, Structure, and Biology (Preceedings of the Eleventh American Peptide Symposium); River, J. E., Marshall, G. R., Eds.; ESCOM Science: Leiden, 1990; pp 369-370.
26. Takahashi, L. H.; Radhakrishnan, R.; Rosenfield, R. E., Jr.; Meyer, E. F., Jr.; Trainor, D. A. Crystal Structure of the Covalent Complex Formed by a Peptidyl α,α-Difluoro-β-keto Amide with Porcine Pancreatic Elastase at 1.78-Å Resolution. J. Am. Chem. Soc. 1989, 111, 3368-3374.
27. Edwards, P. D.; Meyer, E. F., Jr.; Vijayalakshmi, J.; Tuthill, P. A.; Andisik, D. A.; Gomes, B.; Strimpler, A. Design, Synthesis and Kinetic Evaluation of a Unique Class of Elastase Inhibitors, the Peptidyl α-Ketobenzoxazoles, 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.
28. Edwards, P. D.; Wolanin, D. J.; Andisik, D. W.; Davis, M. W. Peptidyl α-Ketoheterocyclic Inhibitors of Human Neutrophil Elastase. 2. Effect of Varying the Heterocyclic Ring on in Vtiro Potency. J. Med. Chem. 1995, 38, 76-85.
29. C-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554.
30. Burkhart, J. P.; Koehl, J. R.; Mehdi, S.; Durham, S. L.; Janusz, M. J.; Huber, E. W.; Angelastro, M. R.; Sunder, S.; Metz, W. A.; Shum, P. W.; Chen, T.-M.; Bey, P.; Cregge, R. J.; Peet, N. P. Inhibition of Human Neutrophil Elastase. 3. An Orally Active Enol Acetate Prodrug. J. Med. Chem. 1995, 38, 223-233.
31. Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Edwards, P. D.; Earley, 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, P. 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.
32. Warner, P.; Green, R. C.; Gomes, B.; Strimpler, A. M. Non-peptidic Inhibitors of Human Leukocyte Elastase. 1. The Design and Synthesis of Pyndone-Containing Inhibitors. J. Med. Chem. 1994, 37, 3090-3099.
33. Damewood, J. R., Jr.; Edwards, P. D.; Feeney, S.; Gomes, B. C.; Steelman, G. B.; Tuthill, P. A.; Williams, J. C.; Warner, P.; Woolson, S. A.; Wolanin, D. J.; Veale, C. A. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 2. Design, Synthesis, and in Vitro Activity of a Series of 3-Amino-6-arylopyridin-2-one Trifluoromethyl Ketones. J. Med. Chem. 1994, 37, 3303-3312.
34. Bernstein, P. R.; Gomes, B. C.; Kosmider, B. J.; Vacek, E. P.; Williams, J. C. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 6. Design of a Potent, Intratracheally Active, Pyridone-Based Trifluoromethyl Ketone. J. Med. Chem. 1995, 38, 212-215.
35. Bernstein, P. R.; Andisik, D.; Bradley, P. K.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; Edwards, P. D.; Feeney, S.; Gomes, B. C.; Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Veale, C. A.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-ray Crystallographic Analysis, and Structure-Activity Relationships for a Series of Orally Active 3-Amino-6-phenylpyridin-2-one Trifluoromethyl Ketones. J. Med. Chem. 1994, 37, 3313-3326.
36. Veale, C. A.; Damewood, J. R., Jr.; Steelman, G. B.; Bryant, C.; Gomes, B.; Williams, J. Non-peptidic Inhibitors of Human Leukocyte Elastase. 4. Design, Synthesis, and in Vitro and in Vivo Activity of a Series of β-Carbolinone-Containing Trifluoromethyl Ketones. J. Med. Chem. 1995, 38, 86-97.
37. Veale, C. A.; Bernstein, P. R.; Bryant, C.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; Feeney, S. W.; Gomes, B.; Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 5. Design, Synthesis and X-ray Crystallography of a Series of Orally Active 5-Aminopyrimidin-6-one-Containing Trifluoromethyl Ketones. J. Med. Chem. 1995, 38, 98-108.
38. Borch, R. F.; Grudzeinbkas, C. V.; Peterson, D. A.; Weber, L. D. A New Synthesis of Substituted 2(1H)-Pyridones. Synthesis of a Potential Camptothecin Intermediate. J. Org. Chem. 1972, 27, 1141-1145.
39. Bergeson, S.; Schwartz, J. A.; Stein, M. M.; Wildonger, R. A.; Edwards, P. D.; Shaw, A.; Trainer, D. A.; Wolanin, D. J. U.S. Patent 4,910,190, 1990; Chem. Abstr. 1991, 114, 123085m.
40. Malachowski, R.; Czornodola, W. Uber Propen-α,α,β-tricarbonsauren. (Regarding Propen-α,α,β-Tricarboxylic Acids.) Chem. Ber. 1935, 68, 363-371.
41. Harwood, L. M. Dry-Column Flash Chromatography. Aldrichimica Acta 1985, 18, 25.