Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.
Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[3,3,4,4,4-penta fluoro-1- (1-methylethyl)-2-oxobutyl]-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-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2- (acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-buteny l]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.
Burkhart
J P
JP
Marion Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Koehl
J R
JR
Mehdi
S
S
Durham
S L
SL
Janusz
M J
MJ
Huber
E W
EW
Angelastro
M R
MR
Sunder
S
S
Metz
W A
WA
Shum
P W
PW
D000085:Acetates; D000818:Animals; D006224:Cricetinae; D006801:Humans; D007659:Ketones; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000737:chemistry*; D011480:Protease Inhibitors / Q000008:administration & dosage*; D013237:Stereoisomerism
D000085:Acetates; D007659:Ketones; D011355:Prodrugs; D011480:Protease Inhibitors; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase