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.
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.
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
J E
JE
Kerrigan
J
J
Oleksyszyn
C M
CM
Kam
J
J
Selzler
J C
JC
Powers
D000595:Amino Acid Sequence; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase; D008969:Molecular Sequence Data; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D003374:Coumarins; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase