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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.

Veale CA, Bernstein PR, Bryant C, Ceccarelli C, Damewood JR, Earley R, Feeney SW, Gomes B, Kosmider BJ, Steelman GB
J Med Chem 38 98-108 (1995)
Cited: 18 times
EuropePMC logo PMID: 7837246

Abstract

The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.

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  11. Synthesis and in vitro evaluation of pseudosaccharinamine derivatives as potential elastase inhibitors. Rode H, Koerbe S, Besch A, Methling K, Loose J, Otto HH. Bioorg. Med. Chem. 14 2789-2798 (2006)
  12. Synthesis, inhibitory activity towards human leukocyte elastase and molecular modelling studies of 1-carbamoyl-4-methyleneaminoxyazetidinones. Macchia B, Gentili D, Macchia M, Mamone F, Martinelli A, Orlandini E, Rossello A, Cercignani G, Pierotti R, Allegretti M, Asti C, Caselli G. Eur J Med Chem 35 53-67 (2000)
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  15. Zinc (II)-Mediated Selective O-Benzylation of 2-Oxo-1,2-Dihydropyridines Systems. Zhou Q, Du F, Liang X, Liu W, Fang T, Chen G. Molecules 23 (2018)


Related citations provided by authors (9)

  1. Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone.. Bernstein PR, Gomes BC, Kosmider BJ, Vacek EP, Williams JC J Med Chem 38 212-5 (1995)
  2. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 4. Design, Synthesis,in Vitro, and in Vivo Activity of a Series of Beta-Carbolinone-Containing Trifluoromethyl Ketones. Veale CA, Damewood JR, Steelman GB, Bryant C, Gomes B, Williams J To be Published -
  3. 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. Bernstein PR, Andisik D, Bradley PK, Bryant CB, Ceccarelli C, Damewood JR, Earley R, Edwards PD, Feeney S, Gomes BC, Kosmider BJ, Steelman GB, Thomas RM, Vacek EP, Veale CA, Williams JC, Wolanin DJ, Woolson SA J. Med. Chem. 37 3313- (1994)
  4. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 2. Design, Synthesis and in Vitro Activity of a Series of 3-Amino-6-Arylpyridin-2-One Trifluoromethyl Ketones. Damewood JR, Edwards PD, Feeney S, Gomes BC, Steelman GB, Tuthill PA, Warner P, Williams JC, Woolson SA, Wolanin D, Veale C J. Med. Chem. 37 3303- (1994)
  5. Nonpeptidic Inhibitors of Human Leukocyte Elastase. 1. The Design and Synthesis of Pyridone-Containing Inhibitors. Warner P, Green RC, Gomes BC, Williams JC J. Med. Chem. 37 3090- (1994)
  6. Design of Orally Active, Nonpeptidic Inhibitors of Human Leukocyte Elastase. Brown FJ, Andisik DW, Bernstein PR, Bryant CB, Ceccarelli C, Damewood JR, Edwards PD, Earley R, Feeney SW, Green RC, Gomes B, Kosmider BJ, Krell R, Shaw A, Steelman GB, Thomas RM, Vacek EP, Veale CA, Tuthill PA, Warner P, Williams JC, Wolanin DJ, Woolson SA J. Med. Chem. 37 1259- (1994)
  7. Design, Synthesis, and Kinetic Evaluation of a Unique Class of Elastase Inhibitors, the Peptidyl Alpha-Ketobenzoxazoles,and the X-Ray Crystal Structure of the Covalent Complex between Porcine Pancreatic Elastase and Ac-Ala-Pro-Val-2-Benzoxazole. Edwards PD, Meyer EF, Vijayalakshmi J, Tuthill PA, Andisik DA, Gomes B, Strimpler A J. Am. Chem. Soc. 114 1854- (1992)
  8. Crystal Structure of the Covalent Complex Formed by a Peptidyl Alpha,Alpha-Difluoro-Beta-Keto Amide with Porcine Pancreatic Elastase at 1.78-Angstrom Resolution. Takahashi LH, Radhakrishnan R, Rosenfield RE, Meyer EF, Trainor DA J. Am. Chem. Soc. 111 3368- (1989)
  9. X-ray diffraction analysis of the inhibition of porcine pancreatic elastase by a peptidyl trifluoromethylketone.. Takahashi LH, Radhakrishnan R, Rosenfield RE, Meyer EF, Trainor DA, Stein M J Mol Biol 201 423-8 (1988)

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