Dutta A S, Gormley J J, McLachlan P F, Major J S
ICI Pharmaceuticals, Alderley Park, Macciesfield, Cheshire, U.K.
J Med Chem. 1990 Sep;33(9):2552-60. doi: 10.1021/jm00171a033.
Cyclic peptide inhibitors of human renin based on a linear peptide, Boc-D-Phe-Cys(Acm)-D-Trp-Leu-OMe (1), were prepared by solution-phase methods. Potent inhibitors were obtained in one series of compounds, Z-Glu-D-Phe-Lys-D-Trp-Leu-OMe (3), in which the D-phenylalanine residue was incorporated in a 15-membered ring structure. Any reductions or enlargements of the ring size led to inactive or less potent peptides. The most potent inhibitor of human renin, Me3CCH2-Glu-D-Phe-Lys-D-Trp-NH(CH2)2CHMe2 (31) (IC50 6.3 x 10(-8) M), was obtained by changing N- and C-terminal parts of pentapeptide 3. It was about 650-fold more potent than linear tetrapeptide I and about 50-fold more potent than cyclic peptide 3. Compound 31 was also 112-fold more potent against human renin than against porcine renin.
基于线性肽Boc-D-苯丙氨酸-半胱氨酸（Acm）-D-色氨酸-亮氨酸-甲酯（1）的人肾素环肽抑制剂通过溶液相法制备。在一系列化合物Z-谷氨酸-D-苯丙氨酸-赖氨酸-D-色氨酸-亮氨酸-甲酯（3）中获得了强效抑制剂，其中D-苯丙氨酸残基被并入15元环结构中。环大小的任何减小或增大都会导致肽无活性或活性降低。通过改变五肽3的N端和C端部分，获得了最有效的人肾素抑制剂Me3CCH2-谷氨酸-D-苯丙氨酸-赖氨酸-D-色氨酸-NH(CH2)2CHMe2（31）（IC50为6.3×10^(-8) M）。它比线性四肽I的活性高约650倍，比环肽（https://pandia.com/t20231113_3857385.html）3的活性高约50倍。化合物31对人肾素的活性也比对猪肾素的活性高112倍。
