Lin J, Toscano P J, Welch J T
Department of Chemistry, University at Albany, Albany, NY 12222, USA.
Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14020-4. doi: 10.1073/pnas.95.24.14020.
Dipeptidyl peptidase IV (EC 3.4.14.5; DPP IV), also known as the leukocyte differentiation antigen CD26 when found as an extracellular membrane-bound proline specific serine protease, cleaves a dipeptide from the N terminus of a polypeptide chain containing a proline residue in the penultimate position. Here we report that known (Z)-Ala-psi[CF=C]-Pro dipeptide isosteres 1 and 2, which contain O-acylhydroxylamines, were isolated as diastereomeric pairs u-1, l-1, and l-2. The effect of each diastereomeric pair as an inhibitor of human placental dipeptidyl peptidase DPP IV has been examined. The inhibition of DPP IV by these compounds is rapid and efficient. The diastereomeric pair u-1 exhibits very potent inhibitory activity with a Ki of 188 nM. Fluoroolefin containing N-peptidyl-O-hydroxylamine peptidomimetics, by virtue of their inhibitory potency and stability, are superior to N-peptidyl-O-hydroxylamine inhibitors derived from an Ala-Pro dipeptide.
二肽基肽酶IV（EC 3.4.14.5；DPP IV），当作为细胞外膜结合的脯氨酸特异性丝氨酸蛋白酶被发现时，也被称为白细胞分化抗原CD26，它从多肽链的N端切割下一个二肽，该多肽链在倒数第二个位置含有一个脯氨酸残基。在此我们报道，已知的含有O - 酰基羟胺的（Z）-丙氨酸-ψ[CF = C]-脯氨酸二肽类似物1和2被分离为非对映体对u - 1、l - 1和l - 2。已经研究了每个非对映体对作为人胎盘二肽基肽酶DPP IV抑制剂的作用。这些化合物对DPP IV的抑制作用迅速且有效。非对映体对u - 1表现出非常强的抑制活性，其抑制常数Ki为188 nM。含氟烯烃的N - 肽基 - O - 羟胺肽模拟物，由于其抑制效力和稳定性，优于源自丙氨酸 - 脯氨酸二肽的N - 肽基 - O - 羟胺抑制剂。
