Hernandez J F, Soleilhac J M, Roques B P, Fournié-Zaluski M C
Département de Chimie Organique, U 266 Inserm, UA 498 CNRS, Paris, France.
J Med Chem. 1988 Sep;31(9):1825-31. doi: 10.1021/jm00117a025.
Peptide retro-inverso modification was applied to the complete hydroxamate inhibitors of the three zinc metallopeptidases (neutral endopeptidase 24-11 (NEP, EC 3.4.24.11), aminopeptidase N (APN, EC 3.4.11.2), and a dipeptidylaminopeptidase (DAP) involved in the in vitro enkephalin degradation by brain tissues. Compounds corresponding to the general formula RN(OH)CO(CH2)nCH(CH2Ph)NHCOCH(R')COOH (n = 0, 1) were synthesized. In the first series of inhibitors (n = 0), the "retro-inverso" modification induced a large decrease in inhibitory potency for NEP as compared to that of the parent compounds. In contrast, the presence of a methylene group between the hydroxamate and CH alpha in the second series (n = 1) led to derivatives with inhibitory potencies in the nanomolar range, similar to their analogues with a natural amide bond. On the other hand, the retro-inverso modification led to a slight improvement in the inhibition of DAP and APN, in the first series of inhibitors, while the inverse result occurred in the second series. Thus, compounds containing an alpha-amino acid moiety in P'1 position behave as weak inhibitors of the three enzymes, with IC50 values in the micromolar range, and compounds bearing a beta-amino acid moiety in the same position are more specific than the parent compounds for NEP inhibition.
肽反向修饰应用于三种锌金属肽酶（中性内肽酶24-11（NEP，EC 3.4.24.11）、氨肽酶N（APN，EC 3.4.11.2）和一种参与脑组织体外脑啡肽降解的二肽基氨肽酶（DAP））的完整异羟肟酸酯抑制剂。合成了通式为RN(OH)CO(CH2)nCH(CH2Ph)NHCOCH(R')COOH（n = 0, 1）的化合物。在第一系列抑制剂（n = 0）中，与母体化合物相比，“反向”修饰导致NEP的抑制活性大幅降低。相反，在第二系列（n = 1）中，异羟肟酸酯和α-碳之间存在亚甲基导致衍生物的抑制活性在纳摩尔范围内，与其具有天然酰胺键的类似物相似。另一方面，在第一系列抑制剂中，反向修饰导致DAP和APN的抑制作用略有改善，而在第二系列中则出现相反的结果。因此，在P'1位置含有α-氨基酸部分的化合物作为这三种酶的弱抑制剂，IC50值在微摩尔范围内，而在相同位置带有β-氨基酸部分的化合物比母体化合物对NEP的抑制更具特异性。
