Eugene L. Giroux

The synthesis of an aminophosphonic acid converting enzyme inhibitor

Abstract The phosphonic acid analog of potent angiotensin-converting enzyme inhibitor MK-422 has been prepared.

Acid-catalyzed O-allylation of β-hydroxy-α-amino acids: an entry into conformationally constrained dipeptide surrogates

Abstract O-Allylation using allyl trichloroimidate 5 was found to be an effective method for the introduction of an acetaldehyde equivalent onto the hydroxyl group of β-hydroxy-α-amino acid derivatives. Rigid oxygen containing tricyclic anti-phenylalanylleucine mimic 1 was efficiently synthesized using this method. This mimetic was further elaborated to provide 7c, a potent inhibitor of angiotensin-1 converting enzyme (ACE).

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.

Fitting Progress Curves in Assays of Slow-Binding Enzyme Inhibitors

Practical aspects of fitting progress curves deriving from assays of slow-binding enzyme inhibitors in order to extract characteristic parameters is briefly discussed. An approach little-used, but which may provide more accurate estimates, is the simultaneous analysis of two assays differing from one another in the order of addition of reactants.