Paper
Mechanism-based isocoumarin inhibitors for human leukocyte elastase. Effect of the 7-amino substituent and 3-alkoxy group in 3-alkoxy-7-amino-4-chloroisocoumarins on inhibitory potency.
Published Feb 3, 1995 · J. Kerrigan, J. Oleksyszyn, C. Kam
Journal of medicinal chemistry
28
Citations
2
Influential Citations
Abstract
A series of 3-alkoxy-7-amino-4-chloroisocoumarins with various 3-alkoxy substituents have been prepared and evaluated as inhibitors of human leukocyte elastase (HLE). In addition, a new series of acyl, urea, and carbamate derivatives of 7-amino-4-chloro-3-methoxyisocoumarin (1), 7-amino-4-chloro-3-propoxyisocoumarin (3), and 7-amino-4-chloro-3-(2-bromoethoxy)isocoumarin (6) have been synthesized. Most of the synthesized compounds are very potent inhibitors of HLE with kobs/[I] values between 10(4) and 10(6) M-1 s-1. Hydrophobic substituents on the 7-amino position of the isocoumarin ring afford the best selectivity and inhibitory potency for HLE. In the 2-bromoethoxy series, compound 24 with a PhNHCONH 7-substituent had a kobs/[I] value of 1.2 x 10(6) M-1 s-1, was very selective for HLE, and was the most potent inhibitor of HLE tested. Of the extended chain L-phenylalanyl derivatives, the Bz-L-Phe compound 66 with a kobs/[I] value of 1.8 x 10(5) M-1 s-1 was the most potent inhibitor of HLE in the 3-methoxyisocoumarin series and was also very selective for HLE. Our results indicate that a high degree of selectivity, along with potency, can be introduced into mechanism-based isocoumarin inhibitors.
In Vitro StudyHydrophobic substituents on the 7-amino position of isocoumarin ring offer the best selectivity and inhibitory potency for human leukocyte elastase, with compounds like PhNHCONH 7-substituent showing the highest potency.
Sign up to use Study Snapshot
Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.
Full text analysis coming soon...