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Inhibition of Human Neutrophil Elastase. 4. Design, Synthesis, X-ray Crystallographic Analysis, and Structure−Activity Relationships for a Series of P 2 -Modified, Orally Active Peptidyl Pentafluoroethyl Ketones

1998; American Chemical Society; Volume: 41; Issue: 14 Linguagem: Inglês

10.1021/jm970812e

1520-4804

Robert J. Cregge, Sherrie Durham, Robert A. Farr, Steven L. Gallion, C. Michelle Hare, Robert V. Hoffman, Michael J. Janusz, Hwa-Ok Kim, Jack R. Koehl, Shujaath Mehdi, William A. Metz, Norton P. Peet, John T. Pelton, Herman Schreuder, Shyam Sunder, Chantal Tardif,

Marine Sponges and Natural Products

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.