SELECTIVITY IN THE INHIBITION OF HIV AND FIV PROTEASE - INHIBITORY AND MECHANISTIC STUDIES OF PYRROLIDINE-CONTAINING ALPHA-KETO AMIDE AND HYDROXYETHYLAMINE CORE STRUCTURES

被引:95
作者
SLEE, DH
LASLO, KL
ELDER, JH
OLLMANN, IR
GUSTCHINA, A
KERVINEN, J
ZDANOV, A
WLODAWER, A
WONG, CH
机构
[1] SCRIPPS CLIN & RES FDN, LA JOLLA, CA 92037 USA
[2] NCI, FREDERICK CANC RES & DEV CTR, MACROMOLEC STRUCT LAB, ABL BASIC RES PROGRAM, FREDERICK, MD 21702 USA
关键词
D O I
10.1021/ja00153a008
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
This paper describes the development of new pyrrolidine-containing alpha-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the alpha-keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold better than the corresponding phosphinic acid derivative as an inhibitor of the HIV protease. The alpha-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activities of hydroxyethylamine isosteres containing modified pyrrolidine derivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine would improve the binding 5-and 25-fold for the trans-isomer. When this strategy was applied to the alpha-keto amide isostere, a cis-benzyl ether at C-4 was found to enhance binding 3-fold. Of the core structures prepared as inhibitors of the HIV protease, none show significant inhibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.
引用
收藏
页码:11867 / 11878
页数:12
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