Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase

Journal of Medicinal Chemistry

Volumn 40, Issue 20, 1997, Pages 3173-3181

  Veale, Chris A ^a   Bernstein, Peter R ^a   Bohnert, Claudia M ^a   Brown, Frederick J ^a   Bryant, Craig ^a   Damewood Jr , James R ^a   Earley, Roger ^a   Feeney, Scott W ^a   Edwards, Philip D ^a   Gomes, Bruce ^a   Hulsizer, James M ^a   Kosmider, Ben J ^a   Krell, Robert D ^a   Moore, Gary ^a   Salcedo, Theodora W ^a   Shaw, Andrew ^a   Silberstein, David S ^a   Steelman, Gary B ^a   Stein, Mark ^a   Strimpler, Anne ^a   Thomas, Roy M ^a   Vacek, Edward P ^a   Williams, Joseph C ^a   Wolanin, Donald J ^a   Woolson, Sheila ^a   more..

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LEUKOCYTE ELASTASE; SERINE PROTEINASE INHIBITOR; UNCLASSIFIED DRUG; ZD 8321;

ANIMAL EXPERIMENT; ARTICLE; DOG; DRUG ACTIVITY; DRUG BIOAVAILABILITY; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME INHIBITION; HAMSTER; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; NONHUMAN; ORAL DRUG ADMINISTRATION; RAT; STEREOCHEMISTRY;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CRICETINAE; DOGS; HUMANS; ISOMERISM; LEUKOCYTE ELASTASE; OLIGOPEPTIDES; RATS; SERINE PROTEINASE INHIBITORS;

EID: 9844256449     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm970250z     Document Type: Article

References (36)

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15. (d) Bernstein, P. B.; Andisik, D.; Bradley, P. K.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; 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-ones. J. Med. Chem. 1994, 37, 3313-3326.
16. (e) Veale, C. A.; Damewood, J. R., Jr.; Steelman, G. B.; Bryant, C. B.; Gomes, B. C.; Williams, J. C. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 4. Design, Synthesis, and Structure-Activity Relationships for a Series of β-Carbolinones. J. Med. Chem. 1995, 38, 86-97.
17. (f) Veale, C. A.; Bernstein, P. R.; Bryant, C. B.; Ceccarelli, C.; Damewood, J. R., Jr.; Earley, R.; Feeney, S. W.; Gomes, B. C.; Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. A. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 5. Design, Synthesis, and X-ray Crystallography of a Series of Orally Active 5-Aminopyrimidin-6-one-Containing Trifluoro-methylketones. J. Med. Chem. 1995, 38, 98-108.
18. Edwards, P. D.; Andisik, D. W.; Bryant, C. A.; Ewing, B.; Gomes, B. C.; Lewis, J. L.; Rakiewicz, D.; Steelman, G. B.; Strimpler, A.; Trainor, D. A.; Tuthill, P. A.; Mauger, R. C.; Veale, C. A.; Wildonger, R. A.; Williams, J. C.; Wolanin, D. J.; Zottola, M. The Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase. J. Med. Chem. 1997, 40, 1876-1885.
19. For work on elastase carried out by other groups, see: (a) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P; Kolb, M.; Neises, B.; Schirlin, D. Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl a Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G. J. Med. Chem. 1990, 33, 394-407. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Janusz, M. J.; Peet, N. P. Janus Compounds: Dual Inhibitors of Proteinases. Bioorg. Med. Chem. Lett. 1993, 3, 525-530. (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O.; Knight, W. B.; Matcock, A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.; Anderson, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.; Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Hanlon, W. A.; Opas, E.; Stolk, J.; Davies, P. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8727-8731. (d) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, 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 Pg-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554. (e) Orally Active b-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure Activity Relationships for 3,3-Dialkylazetidin-2-ones. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hnad, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462.
20. For work on elastase carried out by other groups, see: (a) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P; Kolb, M.; Neises, B.; Schirlin, D. Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl a Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G. J. Med. Chem. 1990, 33, 394-407. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Janusz, M. J.; Peet, N. P. Janus Compounds: Dual Inhibitors of Proteinases. Bioorg. Med. Chem. Lett. 1993, 3, 525-530. (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O.; Knight, W. B.; Matcock, A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.; Anderson, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.; Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Hanlon, W. A.; Opas, E.; Stolk, J.; Davies, P. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8727-8731. (d) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, 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 Pg-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554. (e) Orally Active b-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure Activity Relationships for 3,3-Dialkylazetidin-2-ones. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hnad, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462.
21. For work on elastase carried out by other groups, see: (a) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P; Kolb, M.; Neises, B.; Schirlin, D. Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl a Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G. J. Med. Chem. 1990, 33, 394-407. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Janusz, M. J.; Peet, N. P. Janus Compounds: Dual Inhibitors of Proteinases. Bioorg. Med. Chem. Lett. 1993, 3, 525-530. (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O.; Knight, W. B.; Matcock, A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.; Anderson, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.; Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Hanlon, W. A.; Opas, E.; Stolk, J.; Davies, P. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8727-8731. (d) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, 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 Pg-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554. (e) Orally Active b-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure Activity Relationships for 3,3-Dialkylazetidin-2-ones. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hnad, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462.
22. For work on elastase carried out by other groups, see: (a) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P; Kolb, M.; Neises, B.; Schirlin, D. Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl a Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G. J. Med. Chem. 1990, 33, 394-407. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Janusz, M. J.; Peet, N. P. Janus Compounds: Dual Inhibitors of Proteinases. Bioorg. Med. Chem. Lett. 1993, 3, 525-530. (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O.; Knight, W. B.; Matcock, A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.; Anderson, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.; Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Hanlon, W. A.; Opas, E.; Stolk, J.; Davies, P. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8727-8731. (d) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, 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 Pg-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554. (e) Orally Active b-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure Activity Relationships for 3,3-Dialkylazetidin-2-ones. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hnad, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462.
23. For work on elastase carried out by other groups, see: (a) Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P; Kolb, M.; Neises, B.; Schirlin, D. Synthesis of Peptidyl Fluoromethyl Ketones and Peptidyl a Keto Esters as Inhibitors of Porcine Pancreatic Elastase, Human Neutrophil Elastase, and Rat and Human Neutrophil Cathepsin G. J. Med. Chem. 1990, 33, 394-407. (b) Angelastro, M. R.; Bey, P.; Mehdi, S.; Janusz, M. J.; Peet, N. P. Janus Compounds: Dual Inhibitors of Proteinases. Bioorg. Med. Chem. Lett. 1993, 3, 525-530. (c) Doherty, J. B.; Shah, S. K.; Finke, P. E.; Dorn, C. P.; Hagmann, W. K.; Hale, J. J.; Kissinger, A. L.; Thompson, K. R.; Brause, K.; Chandler, G. O.; Knight, W. B.; Matcock, A. L.; Ashe, B. M.; Weston, H.; Gale, P.; Mumford, R. A.; Anderson, O. F.; Williams, H. R.; Nolan, T. E.; Frankenfield, D. L.; Underwood, D.; Vyas, K. P.; Kari, P. H.; Dahlgren, M. E.; Mao, J.; Fletcher, D. S.; Dellea, P. S.; Hand, K. M.; Osinga, D. G.; Peterson, L. B.; Williams, D. T.; Metzger, J. M.; Bonney, R. J.; Humes, J. L.; Pacholok, S. P.; Hanlon, W. A.; Opas, E.; Stolk, J.; Davies, P. Chemical, biochemical, pharmacokinetic, and biological properties of L-680,833: A potent, orally active monocyclic β-lactam inhibitor of human polymorphonuclear leukocyte elastase Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8727-8731. (d) Angelastro, M. R.; Baugh, L. E.; Bey, P.; Burkhart, 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 Pg-Val-Pro-Val Pentafluoroethyl Ketones. J. Med. Chem. 1994, 37, 4538-4554. (e) Orally Active b-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure Activity Relationships for 3,3-Dialkylazetidin-2-ones. Finke, P. E.; Shah, S. K.; Fletcher, D. S.; Ashe, B. M.; Brause, K. A.; Chandler, G. O.; Dellea, P. S.; Hnad, K. M.; Maycock, A. L.; Osinga, D. G.; Underwood, D. J.; Weston, H.; Davies, P.; Doherty, J. B. J. Med. Chem. 1995, 38, 2449-2462.
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32. The rate of chemical degradation, extrapolated to 25 °C, indicates a half-life for 1h of 0.7 days at pH 10, 5.5 days at pH 8, 34 days at pH 6, and 120 days at pH 4. Conversely compound 1c was found to completely decompose at pH 10 in less than 1 h.
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35. Physical property characterization consisted of evaluation of aqueous solubility, crystallinity, and hygroscopicity.
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