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

Citation
Rj. Cregge et al., 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, Journal of medicinal chemistry, 41(14), 1998, pp. 2461-2480
Citations number
55
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry Medicinal
ISSN journal
0022-2623
Volume
41
Issue
14
Year of publication
1998
Pages
2461 - 2480
Database
ISI
SICI code
0022-2623(1998)41:14<2461:IOHNE->2.0.ZU;2-R
Abstract
A series of P-2-modified, orally active peptidic inhibitors of human n eutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-b ased inhibitors were designed using pentafluoroethyl ketone 1 as a mod el. Rational structural modifications were made at the P-3, P-2, and a ctivating group (A(G)) portions of 1 based on structure-activity relat ionships (SAR) developed from in vitro (measured K-i) data and. inform ation provided by modeling studies that docked inhibitor 1 into the ac tive site of HNE. The modeling-based design was corroborated with X-ra y crystallographic analysis of the complex between 1 and porcine pancr eatic elastase (PPE) and subsequently the complex between 1 and HNE.