175012-22-3Relevant academic research and scientific papers
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
Cregge, Robert J.,Durham, Sherrie L.,Farr, Robert A.,Gallion, Steven L.,Hare, C. Michelle,Hoffman, Robert V.,Janusz, Michael J.,Kim, Hwa-Ok,Koehl, Jack R.,Mehdi, Shujaath,Metz, William A.,Peet, Norton P.,Pelton, John T.,Schreuder, Herman A.,Sunder, Shyam,Tardif, Chantal
, p. 2461 - 2480 (2007/10/03)
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 (A(G)) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured K(i)) 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.
Inhibition of Human Neutrophil Elastase. 3. An Orally Active Enol Acetate Prodrug
Burkhart, Joseph P.,Koehl, Jack R.,Mehdi, Shujaath,Durham, Sherrie L.,Janusz, Michael J.,et al.
, p. 223 - 233 (2007/10/02)
Several analogs of N--L-valyl-N--L-prolinamide (1), in which the chiral center of the P1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE).Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P1.In vitro studies, in the presence of added esterase, and 19F NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo.The ED50 value for (E)-N--L-valyl-N--L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.
Inhibition of human neutrophil elastase with peptidyl electrophilic ketones. 2. Orally active p(G)-Val-Pro-Val pentafluoroethyl ketones
Angelastro,Baugh,Bey,Burkhart,Chen,Durham,Hare,Huber,Janusz,Koehl,Marquart,Mehdi,Peet
, p. 4538 - 4553 (2007/10/02)
Valylprolylvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lun
