Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.

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Burkhart JP, Koehl JR, Mehdi S, Durham SL, Janusz MJ, Huber EW, Angelastro MR, Sunder S, Metz WA, Shum PW, et al.

Inhibition of human neutrophil elastase. 3. An orally active enol acetate prodrug.

J Med Chem. 1995 Jan 20;38(2):223-33.

PubMed ID

7830264 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Mdl 101,146	Neutrophil elastase	Ki (nM)	25	N/A	N/A	Details