Interaction of angiotensin I-converting enzyme with two potent tricyclic inhibitors

Inhibition of rabbit lung angiotensin I-converting enzyme was studied with two inhibitors that combined tricyclic mimics of a substrate C-terminal dipeptide recognition unit with a 4-phenylbutanoic acid fragment. The overall inhibition constant for [4S-[4 alpha, 7 alpha(R*),12b beta]]-7-[S-(1-carboxy-3-phenylpropyl) amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido[2,1-a] [2] benzazepine-4-carboxylic acid (MDL 27,088) was approximately 4 pM, whereas that for [4R-[4 alpha, 7 alpha(S*), 12b beta]]-7-[S-(1-carboxy-3-phenylpropyl)amino]-3,4,6,7,8, 12b-hexahydro-6-oxo-1H-[1,4]thiazino[3,4-a] [2]benzazepine-4-carboxylic acid (MDL 27,788) was estimated to be 46 pM. The formation of an initial complex of target enzyme and MDL 27,088 and its slower isomerization to a second complex were characterized kinetically. Both compounds appear to be among the most potent inhibitors known for this enzyme.