863480-37-9Relevant academic research and scientific papers
Design, synthesis, and enzymatic evaluation of N1-acyloxyalkyl- and N1-oxazolidin-2,4-dion-5-yl-substituted β-lactams as novel inhibitors of human leukocyte elastase
Moreira, Rui,Santana, Ana Bela,Iley, Jim,Neres, Jo?o,Douglas, Kenneth T.,Horton, Peter N.,Hursthouse, Michael B.
, p. 4861 - 4870 (2007/10/03)
Human leukocyte elastase (HLE) is a serine protease that very efficiently degrades various tissue matrix proteins such as elastin. The imbalance between HLE and its endogenous inhibitors leads to excessive elastin proteolysis and is considered to be respo
Orally active β-lactam inhibitors of human leukocyte elastase. 2. Effect of C-4 substitution
Hagmann,Kissinger,Shah,Finke,Dorn,Brause,Ashe,Weston,Maycock,Knight,Dellea,Fletcher,Hand,Osinga,Davies,Doherty
, p. 771 - 777 (2007/10/02)
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.
