Kerrigan J E, Oleksyszyn J, Kam C M, Selzler J, Powers J C
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332-0400.
J Med Chem. 1995 Feb 3;38(3):544-52. doi: 10.1021/jm00003a017.
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.
已制备了一系列具有不同3-烷氧基取代基的3-烷氧基-7-氨基-4-氯异香豆素，并将其作为人白细胞弹性蛋白酶（HLE）的抑制剂进行了评估。此外，还合成了7-氨基-4-氯-3-甲氧基异香豆素（1）、7-氨基-4-氯-3-丙氧基异香豆素（3）和7-氨基-4-氯-3-(2-溴乙氧基)异香豆素（6）的一系列新的酰基、脲和氨基甲酸酯衍生物。大多数合成化合物是HLE的强效抑制剂，其kobs/[I]值在10(4)至10(6) M-1 s-1之间。异香豆素环7-氨基位置上的疏水取代基对HLE具有最佳的选择性和抑制效力。在2-溴乙氧基系列中，具有PhNHCONH 7-取代基的化合物24的kobs/[I]值为1.2 x 10(6) M-1 s-1，对HLE具有高度选择性，是测试的HLE最有效抑制剂。在延伸链L-苯丙氨酰衍生物中，kobs/[I]值为1.8 x 10(5) M-1 s-1的Bz-L-Phe化合物66是3-甲氧基异香豆素系列中HLE最有效的抑制剂，对HLE也具有高度选择性。我们的结果表明，可以将高度的选择性以及效力引入基于机制的异香豆素抑制剂中。
