1EAT

NONPEPTIDIC INHIBITORS OF HUMAN LEUKOCYTE ELASTASE. 5. DESIGN, SYNTHESIS, AND X-RAY CRYSTALLOGRAPHY OF A SERIES OF ORALLY ACTIVE 5-AMINO-PYRIMIDIN-6-ONE-CONTAINING TRIFLUOROMETHYLKETONES

Summary for 1EAT

• Entry DOI: 10.2210/pdb1eat/pdb
• Descriptor: PORCINE PANCREATIC ELASTASE, SODIUM ION, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase (serine protease)
• Biological source: Sus scrofa (pig)
• Cellular location: Secreted: P00772
• Total number of polymer chains: 1
• Total formula weight: 26632.62

Authors

Ceccarelli, C. (deposition date: 1994-11-22, release date: 1995-02-07, Last modification date: 2024-10-23)

Primary citation

Veale, C.A.,Bernstein, P.R.,Bryant, C.,Ceccarelli, C.,Damewood Jr., J.R.,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., 38:98-108, 1995

PubMed 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.

PubMed: 7837246
DOI: 10.1021/jm00001a015

Experimental method

X-RAY DIFFRACTION (2 Å)