Belyaev A, Zhang X, Augustyns K, Lambeir A M, De Meester I, Vedernikova I, Scharpé S, Haemers A
Departments of Pharmaceutical Chemistry and Medical Biochemistry, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerp, Belgium.
J Med Chem. 1999 Mar 25;42(6):1041-52. doi: 10.1021/jm981033g.
The previously reported diphenyl 1-(S)-prolylpyrrolidine-2(R, S)-phosphonate (5) was used as a lead compound for the development of potent and irreversible inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). The synthesis of a series of diaryl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonates with different substituents on the aryl rings (hydroxyl, methoxy, acylamino, sulfonylamino, ureyl, methoxycarbonyl, and alkylaminocarbonyl) started from the corresponding phosphites. A good correlation was found between the electronic properties of the substituent and the inhibitory activity and stability. The most striking divergence of this correlation was the high potency combined with a high stability of the 4-acetylamino-substituted derivative 11e. This compound shows low cytotoxicity in human peripheral blood mononuclear cells and also has favorable properties in vivo. Therefore bis(4-acetamidophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate (11e) is considered as a major improvement and will be a highly valuable DPP IV inhibitor for further studies on the biological function of the enzyme and the therapeutic value of its inhibition.
先前报道的二苯基 1-(S)-脯氨酰基吡咯烷-2(R,S)-膦酸酯(5)被用作开发二肽基肽酶IV(DPP IV，EC 3.4.14.5)强效不可逆抑制剂的先导化合物。从相应的亚磷酸酯开始合成了一系列在芳环上具有不同取代基(羟基、甲氧基、酰氨基、磺酰氨基、脲基、甲氧基羰基和烷基氨基羰基)的二芳基 1-(S)-脯氨酰基吡咯烷-2(R,S)-膦酸酯。发现取代基的电子性质与抑制活性和稳定性之间存在良好的相关性。这种相关性最显著的差异是4-乙酰氨基取代衍生物11e具有高效力和高稳定性。该化合物在人外周血单核细胞中显示出低细胞毒性，并且在体内也具有良好的性质。因此，双(4-乙酰氨基苯基)1-(S)-脯氨酰基吡咯烷-2(R,S)-膦酸酯(11e)被认为是一个重大改进，将成为一种非常有价值的DPP IV抑制剂，用于进一步研究该酶的生物学功能及其抑制的治疗价值。
