Jp. Burkhart et al., INHIBITION OF HUMAN NEUTROPHIL ELASTASE .3. AN ORALLY-ACTIVE ENOL ACETATE PRODRUG, Journal of medicinal chemistry, 38(2), 1995, pp. 223-233
Several analogs of fluoro-1-(1-methylethyl)-2-oxobutyl]-L-prolinamide
(1), in which the chiral center of the P-1 residue has been eliminated
, were synthesized and tested as inhibitors of human neutrophil elasta
se (HNE). Observations made during the course of this work led to the
development of a single-step, stereoselective synthesis of E-enol acet
ate derivatives from HNE inhibitors containing a mixture of epimers at
P-1. In, vitro studies, in the presence of added esterase, and F-19 N
MR studies, in biological media, indicated that the E-enol acetate der
ivatives should act as prodrugs in vivo. The ED(50) value for afluoro-
1-(1-methylethyl)-1-butenyl]-L-prolinamide (20), when administered ora
lly in the hamster lung hemorrhage model, was 9 mg/kg.