The three dimensional requirements for inhibition of ACE (angiotensin converting enzyme) were investigated in order to facilitate design of a more potent and selective antihypertensive agent. 2. All compounds designed possessed a bicyclic unit incorporating carboxylate and amidic carbonyl groups together with a thiol-bearing side chain. 3. NMR spectroscopy of the bicyclic units and molecular mechanics calculations enabled the possible positions of the thiol group to be studied. 4. Determination of the positions of the thiol group conferring best inhibition in the active site of ACE permitted the probable location of the active site zinc ion to be identified. The intention was to replace the thiol side chain with a homophenylalanine unit to bind to the zinc ion and also to occupy the S1 site which fits the Phe8 side chain of angiotensin I. 5. Examination of a torsional angle psi in a compound possessing poor inhibitory potency indicated correspondence to a high energy conformation of alanylproline. The bicyclic unit was modified to incorporate a seven-instead of a six-membered ring to bring psi into the range of an accessible conformation of alanylproline. The corresponding IC50 resulting indicated that psi was closer to that of the active conformations of enalaprilat and captopril. 6. Removal of one carbonyl improved the ACE inhibitory potency further. 7. The postulated active conformation of cilazaprilat is presented.
