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

1EAT の概要

• エントリーDOI: 10.2210/pdb1eat/pdb
• 分子名称: PORCINE PANCREATIC ELASTASE, SODIUM ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: hydrolase (serine protease)
• 由来する生物種: Sus scrofa (pig)
• 細胞内の位置: Secreted: P00772
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26632.62

構造登録者

Ceccarelli, C. (登録日: 1994-11-22, 公開日: 1995-02-07, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)