Orally active beta-lactam inhibitors of human leukocyte elastase. 2. Effect of C-4 substitution.
J Med Chem
; 36(6): 771-7, 1993 Mar 19.
Article
em En
| MEDLINE
| ID: mdl-8459404
ABSTRACT
The effect of changing the C-4 substituent of 3,3-diethyl-1-[(benzylamino)carbonyl]-2-azetidinone on inhibition of HLE and in a model of HLE-induced lung damage in hamsters was explored. Substituents at this position do not appear to interact strongly with HLE with the most potent compounds having k(obs)/[I] = 6900 M-1 s-1. However, substituents at this position had a marked effect on in vivo activity. The greatest oral activity in the lung hemorrhage assay was achieved with C-4 aryl carboxylic acid ethers (60-85% inhibition at 30 mg/kg po). Based upon the established mechanism of inhibition by these compounds, the C-4 substituent would be released, and therefore, the pharmacological potential of these C-4 substituents was of considerable concern. Fortunately, compounds containing 4-hydroxybenzoic acid and 4-hydroxyphenylacetic acid ethers at C-4 were among the most active analogs. These phenolic acids are also found as urinary metabolites in healthy humans. Other heteroaryls at C-4 were also orally active in this model despite relatively modest enzyme activity.
Buscar no Google
Base de dados:
MEDLINE
Assunto principal:
Monobactamas
/
Elastase Pancreática
Limite:
Animals
Idioma:
En
Ano de publicação:
1993
Tipo de documento:
Article