- Orally active β-lactam inhibitors of human leukocyte elastase. 2. Effect of C-4 substitution
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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,Kissinger,Shah,Finke,Dorn,Brause,Ashe,Weston,Maycock,Knight,Dellea,Fletcher,Hand,Osinga,Davies,Doherty
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p. 771 - 777
(2007/10/02)
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- Orally Active β-Lactam Inhibitors of Leukocyte Elastase-1. Activity of 3,3-Diethyl-2-azetidinones
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A thorough analysis of the mechanism of inhibition of human leukocyte elastase (HLE) by a monocyclic β-lactam and the mechanism of β-lactam hydrolysis led to the preparation of potent and highly stable inhibitors of HLE.This work led to the identification of 4--3,3-diethyl-1-carbonyl>-2-azetidinone (2) as the first orally active inhibitor of human leukocyte elastase (HLE).Analogs of 2 with different substituents on the urea N were synthesized and evaluated for their activity in vitro against HLE as well as in vivo in a hamster lung hemorrhage model.Compounds with a methyl or a methoxy group in the para position of the benzene ring were very potent in both assays.The results are discussed on the basis of the proposed model for the binding of this class of inhibitors to HLE and a possible mechanism of inhibition is presented.
- Shah, Shrenik K.,Dorn, Conrad P.,Finke, Paul E.,Hale, Jeffrey J.,Hagmann, William K.,et al.
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p. 3745 - 3754
(2007/10/02)
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