title: 6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid as a core structure for specific inhibitors of human leukocyte elastase.
abstract: Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and alpha-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (k(i)/K(I) = 107 000 M(-1). s(-1) for 4c) and thrombin (k(i)/K(I) = 7 200 M(-1).s(-1) for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, alpha-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (k(i)/K(I) = 107 400 M(-1). s(-1) for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), human leukocyte elastase was specifically inhibited suggesting that this new series of human leukocyte elastase inhibitors may be of potential therapeutic interest in degradative and degenerative processes involving this enzyme.
authors.affiliation: Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, Département de Biologie Supramoléculaire et Cellulaire, Institut Jacques Monod, Universités Paris VI and Paris VII, Tour 43, 2, place Jussieu, F-75251 Paris Cedex 05, France.
authors.forename: C
authors.initials: C
authors.lastname: Doucet
authors.forename: L
authors.initials: L
authors.lastname: Pochet
authors.forename: N
authors.initials: N
authors.lastname: Thierry
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: M
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D004791:Enzyme Inhibitors; D019272:Leukocyte Elastase