Orally active beta-lactam inhibitors of human leukocyte elastase. 2. Effect of C-4 substitution.
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.
Hagmann
W K
WK
Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, New Jersey 07065.
Kissinger
A L
AL
Shah
S K
SK
Finke
P E
PE
Dorn
C P
CP
Brause
K A
KA
Ashe
B M
BM
Weston
H
H
Maycock
A L
AL
Knight
W B
WB
D000284:Administration, Oral; D000818:Animals; D006224:Cricetinae; D006470:Hemorrhage / Q000517:prevention & control; D019272:Leukocyte Elastase; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008997:Monobactams / Q000138:chemical synthesis* / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000633:toxicity; D013329:Structure-Activity Relationship
D008997:Monobactams; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase