Holladay M W, Salituro F G, Rich D H
J Med Chem. 1987 Feb;30(2):374-83. doi: 10.1021/jm00385a020.
Synthetic details for the preparation of a series of hydroxyethylene and ketomethylene dipeptide isosteres with control of stereochemistry at C(2) are described. Incorporation of the isosteres into peptide sequences derived from pepstatin afforded potent inhibitors of the aspartic protease porcine pepsin. When Leu-OH-Ala or Leu-OH-Phe was substituted for statine [3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), inhibitors equipotent to the parent compound were obtained, whereas Leu-OH-Gly was a much less effective replacement for statine. A similar trend was evident in the corresponding ketones. The finding that structural features for good substrates do not closely parallel those for good inhibitors is discussed.
本文描述了一系列在C(2)处具有立体化学控制的羟乙烯和酮亚甲基二肽类似物的合成细节。将这些类似物引入源自胃蛋白酶抑制剂的肽序列中，得到了天冬氨酸蛋白酶猪胃蛋白酶的有效抑制剂。当用亮氨酰-羟基丙氨酸或亮氨酰-羟基苯丙氨酸取代静菌氨酸（(3S,4S)-4-氨基-3-羟基-6-甲基庚酸）时，得到了与母体化合物等效的抑制剂，而亮氨酰-羟基甘氨酸作为静菌氨酸的替代物效果则差得多。在相应的酮类化合物中也观察到了类似的趋势。本文还讨论了良好底物的结构特征与良好抑制剂的结构特征并非紧密平行这一发现。
