... Eur. J. Org. Chem., (2010), pp. 10171020. 5 W. Jiang, C. Chen, D. Marinkovic, JA Tran, CW Ch... more ... Eur. J. Org. Chem., (2010), pp. 10171020. 5 W. Jiang, C. Chen, D. Marinkovic, JA Tran, CW Chen, LM Arellano, NS White and FC Tucci. J. Org. Chem., 70 (2005), p. 8924. HA Rajapakse, MB Young, H. Zhu, S. Charlton and NN Tsou. Tetrahedron Lett., 46 (2005), p. 8909. ...
Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is r... more Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous alpha1-proteinase inhibitor (alpha1Pi). Nevertheless, under pathological conditions, alpha1i is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/alpha1Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil-released oxidants, would undoubtedly represent an important advance in the management of neutrophil-mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation o...
... Elastase D. Andisik, a P. Bemstein," F. Brown, a C. Bryant, a C. Ceccarelli, a j. Damewo... more ... Elastase D. Andisik, a P. Bemstein," F. Brown, a C. Bryant, a C. Ceccarelli, a j. Damewood," P. Edwards, ~ S. Feeney, "B. Gomes, a R. Green, a B. Kosmider, a A. Shaw, a a. Steelman, a R.Thomas," P. Tuthill, a ... 8. Jackson AH, Hill SL, Afford SC, Stockley RA (1984) J. Respir. Dis. ...
Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal... more Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.
Page 1. J. Med. Chem. 1994,37, 3303-3312 3303 Nonpeptidic Inhibitors of Human Leukocyte Elastase.... more Page 1. J. Med. Chem. 1994,37, 3303-3312 3303 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 James R. Damewood, Jr.,? Philip D. Edwards,? Scott Feeney,? ...
Page 1. Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems KC Ni... more Page 1. Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems KC Nicolaou,* Guo-qiang Shi, Janet L. Gunzner, Peter Gärtner, Paul A. Wallace, Michael A. Ouellette, Shuhao Shi, Mark E. Bunnage ...
... Eur. J. Org. Chem., (2010), pp. 10171020. 5 W. Jiang, C. Chen, D. Marinkovic, JA Tran, CW Ch... more ... Eur. J. Org. Chem., (2010), pp. 10171020. 5 W. Jiang, C. Chen, D. Marinkovic, JA Tran, CW Chen, LM Arellano, NS White and FC Tucci. J. Org. Chem., 70 (2005), p. 8924. HA Rajapakse, MB Young, H. Zhu, S. Charlton and NN Tsou. Tetrahedron Lett., 46 (2005), p. 8909. ...
Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is r... more Neutrophils release elastase, which is known secondarily to cause tissue damage. However, it is rapidly inactivated by the endogenous alpha1-proteinase inhibitor (alpha1Pi). Nevertheless, under pathological conditions, alpha1i is inactivated by oxidants released from neutrophils, resulting in an excess of elastase at the site of inflammation. This elastase/alpha1Pi imbalance has been implicated as a pathogenic factor in cystic fibrosis, acute respiratory distress syndrome, and emphysema. Elastase inhibitors, which do not interfere with the microbicidal activity of neutrophils and are resistant to neutrophil-released oxidants, would undoubtedly represent an important advance in the management of neutrophil-mediated tissue injury. We report that a new family of elastase inhibitors ICI200355 and ZD0892 was found to be resistant toward superoxide, hypochlorous acid, hydrogen peroxide, hydroxyl radical, and peroxynitrite mediated degradation as well as having no effect on the formation o...
... Elastase D. Andisik, a P. Bemstein," F. Brown, a C. Bryant, a C. Ceccarelli, a j. Damewo... more ... Elastase D. Andisik, a P. Bemstein," F. Brown, a C. Bryant, a C. Ceccarelli, a j. Damewood," P. Edwards, ~ S. Feeney, "B. Gomes, a R. Green, a B. Kosmider, a A. Shaw, a a. Steelman, a R.Thomas," P. Tuthill, a ... 8. Jackson AH, Hill SL, Afford SC, Stockley RA (1984) J. Respir. Dis. ...
Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal... more Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.
Page 1. J. Med. Chem. 1994,37, 3303-3312 3303 Nonpeptidic Inhibitors of Human Leukocyte Elastase.... more Page 1. J. Med. Chem. 1994,37, 3303-3312 3303 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 James R. Damewood, Jr.,? Philip D. Edwards,? Scott Feeney,? ...
Page 1. Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems KC Ni... more Page 1. Total Synthesis of Brevetoxin A: Part 3: Construction of GHIJ and BCDE Ring Systems KC Nicolaou,* Guo-qiang Shi, Janet L. Gunzner, Peter Gärtner, Paul A. Wallace, Michael A. Ouellette, Shuhao Shi, Mark E. Bunnage ...
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