Inhibition of serine proteases by benzoxazinones: effects of electron withdrawal and 5-substitution.

Abstract:

:A series of substituted 4H-3,1-benzoxazin-4-ones have been made and assayed as inhibitors of human leukocyte elastase (HLE) and other serine proteases. The benzoxazinones are kinetically competitive, alternate substrate inhibitors that inhibit by acylation and slow deacylation. Two structure-activity relationships have been found which are consistent with this mechanism. First, electron withdrawal at position 2 gives better inhibition (lower Ki values) because acylation rates are increased while deacylation is relatively unaffected. Second, benzoxazinones with methyl or ethyl substitution at position 5 are better inhibitors of HLE because the acyl enzymes formed from these compounds are 2,6-disubstituted benzoic acid esters and their deacylation is sterically hindered.

authors

Spencer RW,Copp LJ,Bonaventura B,Tam TF,Liak TJ,Billedeau RJ,Krantz A

doi

10.1016/0006-291x(86)90724-2

subject

Has Abstract

pub_date

1986-11-14 00:00:00

pages

928-33

issue

3

eissn

0006-291X

issn

1090-2104

pii

0006-291X(86)90724-2

journal_volume

140

pub_type

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