Design of (ω‐N‐(O‐acyl)hydroxy amid) aminodicarboxylic acid pyrrolidides as potent inhibitors of proline‐specific peptidases

FEBS Letters - Tập 320 - Trang 23-27 - 1993
H.-U. Demuth1, D. Schlenzig1, A. Schierhorn1, G. Grosche1, M.-P. Chapot-Chartier2, J.-C. Gripon2
1Department of Biochemistry, Martin-Luther-University of Halle, Weinbergweg 16 A, D-O-Halle (Saale, Germany
2Unité d'Enzymologie, Station de Recherches Laitières, INRA, F-78352 Jouy-en Josas Cedex, France

Tóm tắt

A novel class of competitive, acylating inhibitors for the proline‐specific peptidases: dipeptidyl peptidase IV, dipeptidyl peptidase II and prolyl endopeptidase, has been developed. The inhibitor molecules combine the efficacy of aminoacyl pyrrolidides and the potential transacylating capability of diacyl hydroxyl amines. The N‐terminal deblocked inhibitors are potent reversible inhibitors of porcine kidney dipeptidyl peptidase IV, human placenta dipeptidyl peptidase II exhibiting K 1 values in the μM range. Boc‐protected (ω‐N‐hydroxy acyl amid) aminodiacarboxylic acid pyrrolidides inhibit substrate hydrolysis by prolyl endopeptidases from different sources competitively reaching K, values of 30 nM to 60 μM. Additionally, α‐N‐BOC‐(ω‐N‐hydroxy acetyl) glutaminyl pyrrolidide modifies human placenta prolyl endopeptidase in a time‐dependent reaction.

Tài liệu tham khảo

10.1016/0014-5793(88)80092-9 10.1016/0024-3205(83)90285-0 10.1016/S0021-9258(19)39656-5 10.1093/oxfordjournals.jbchem.a123682 10.1002/bip.360240119 10.1016/S0021-9258(18)45502-0 10.1016/0167-4838(88)90067-2 10.1248/bpb1978.10.730 10.1016/0014-5793(90)80084-V 10.1111/j.1471-4159.1991.tb08160.x 10.1042/bj2230255 10.4049/jimmunol.144.8.2908 10.1016/0009-8981(92)90042-O 10.3109/14756368809040718 10.1042/bj2630861 10.1016/0167-4838(89)90088-5 10.3109/14756369009035834 Demuth H.-U., 1988, Pharmazie, 43, 262 10.1135/cccc19860234 Wünsch E., 1974, Methods in Organic Chemistry 10.1111/j.1365-2672.1990.tb02886.x Demuth H.-U., 1989, J. Enzyme Inhib., 4, 249 10.3109/14756369109069060 10.1515/bchm3.1991.372.1.305 10.1515/bchm3.1990.371.2.1159
Thông tin
Thông tin xuất bản

FEBS Letters

Tập 320

23-27

Thông tin tác giả