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-alkox y substituents have been prepared and evaluated as inhibitors of human leukocyte elastase (HLE). In addition, a new series of acyl, urea, an d carbamate derivatives of 7-amino-4-chloro-3-methoxyisocoumarin (1), 7-amino-4-chloro-3-propoxyisocoumarin (3), and 7-amino-4-chloro-3-(2-b romoethoxy)isocoumarin (6) have been synthesized. Most of the synthesi zed compounds are very potent inhibitors of HLE with k(obs)/[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 a nd inhibitory potency for HLE. In the 2-bromoethoxy series, compound 2 4 with a PhNHCONH 7-substituent had a k(obs)/[I] value of 1.2 x 10(6) M(-1) s(-1), was very selective for HLE, and was the most potent inhib itor of HLE tested. Of the extended chain L-phenylalanyl derivatives, the Bz-L-Phe compound 66 with a k(obs)/[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 i nto mechanism-based isocoumarin inhibitors.