Inhibition of human neutrophil elastase. 4. Design, synthesis, X-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluoroethyl ketones

Journal of Medicinal Chemistry
R J CreggeC Tardif

Abstract

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

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Citations

Dec 31, 2003·Bioorganic & Medicinal Chemistry·Stéphane GérardJacqueline Marchand-Brynaert
Dec 7, 2002·Bioorganic & Medicinal Chemistry Letters·Takayoshi KinoshitaToshiji Tada
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Apr 29, 2010·The FEBS Journal·Eric HajjarNathalie Reuter
Oct 10, 2020·Frontiers in Chemistry·Letizia CrocettiMark T Quinn
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