ABSTRACT
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.
