Inhibition of human neutrophil elastase with peptidyl electrophilic ketones. 2. Orally active PG-Val-Pro-Val pentafluoroethyl ketones.
Valylprolyvalyl 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 lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM.
Angelastro
M R
MR
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Baugh
L E
LE
Bey
P
P
Burkhart
J P
JP
Chen
T M
TM
Durham
S L
SL
Hare
C M
CM
Huber
E W
EW
Janusz
M J
MJ
Koehl
J R
JR
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D006470:Hemorrhage / Q000188:drug therapy; D006801:Humans; D007659:Ketones / Q000032:analysis / Q000138:chemical synthesis / Q000494:pharmacology*; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D051381:Rats; D013329:Structure-Activity Relationship
D007659:Ketones; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase