Ojima I, Jameison F A, Pete B, Radunz H, Schittenhelm C, Lindner H J, Emith A E
Department of Chemistry, State University of New York at Stony Brook 11794-3400.
Drug Des Discov. 1994 Feb;11(2):91-113.
A series of trifluoromethyl-containing analogs of captopril as well as analogs and homologs of enalaprilat were synthesized and evaluated for inhibition of angiotensin converting enzyme (ACE). It was found that direct substitution of trifluoromethyl for methyl produced a very potent captopril analog with an IC50 of 3 x 10(-10) M in vitro. Hydrophobicity and conformational effects of trifluoromethyl group are among the reasons accounting for this activity. Structure-activity relationship is studied based on molecular mechanics calculations using a II-SCF-molecular mechanics program (PIMM) as well as SYBYL molecular mechanics program. It was found that simultaneous incorporation of trifluoromethyl and an indoline residue unexpectedly yielded a less potent captopril analog (IC50 = 8 x 10(-8) M). Enalaprilat analogs derived from replacement of the alanine residue with trifluoronorvaline and trifluoronorleucine residues gave moderately potent compounds (IC50 = 2-6 x 10(-8) M). The structure-activity relationship for these fluoroenalaprilat analogs is discussed in comparison with known analogs.
合成了一系列含三氟甲基的卡托普利类似物以及依那普利拉的类似物和同系物，并对其抑制血管紧张素转换酶（ACE）的活性进行了评估。研究发现，直接用三氟甲基取代甲基可产生一种非常有效的卡托普利类似物，其体外IC50为3×10⁻¹⁰ M。三氟甲基的疏水性和构象效应是导致这种活性的部分原因。基于使用II-SCF分子力学程序（PIMM）以及SYBYL分子力学程序进行的分子力学计算，研究了构效关系。结果发现，同时引入三氟甲基和吲哚啉残基意外地产生了一种活性较低的卡托普利类似物（IC50 = 8×10⁻⁸ M）。用三氟正缬氨酸和三氟正亮氨酸残基取代丙氨酸残基得到的依那普利拉类似物具有中等活性（IC50 = 2 - 6×10⁻⁸ M）。与已知类似物相比，讨论了这些含氟依那普利拉类似物的构效关系。
