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
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
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.