Angiotensin converting enzyme conformational restriction

Captopril 678 and enalapril 679 are potent angiotensin converting enzyme (ACE) inhibitors used as antihypertensives. Molecular manipulation based on the enzyme model led to the discovery of some perspective bicyclic structures, for example, cilazapril 680 and compound 681, highly active antihypertensives in vivo. Compound 681 belongs to the most potent conformationally restricted ACE inhibitors and is often used as a model for molecular modeling studies <1996JA8231>. 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

Thorsett, E. D. Conformationally restricted inhibitors of angiotensin converting enzyme. In Actualites de Chimie Therapeutique... 

Thorsett, E.D. (1986) Conformationally restricted inhibitors of angiotensin converting enzyme. In Combet-Famoux, C. (ed.). Actualites de Chimie Therapeutique, pp. 257 - 268. Societe de Chimie Therapeutique, Chatenay-Malabty. 

Flynn, G.A., Giroux, E.L. and Dage, R.C. (1987) An acyl-iminium ion cycUzation route to a novel conformationally restricted dipeptide mimic applications to angiotensin-converting enzyme inhibition. J. Am. Chem. Soc. 109 7914-7915. 

G. A. Flynn, E. L. Giroux, and R. C. Dage,/. Am. Chem. Soc., 109, 7914 (1987). An Acyl-Iminium Ion Cyclization Route to a Novel Conformationally Restricted Dipeptide Mimic Applications to Angiotensin-Converting Enzyme Inhibition. 

Flynn, G. A., Beight, D. W., Mehdi, S., Koehl, J. R., Giroux, E. L., French, J. E, Hake, R W., Dage, R. C. Application of a conformation-ally restricted phe-leu dipeptide mimetic to the design of a combined inhibitor of angiotensin I-converting enzyme and neutral endopepti-dase 24.11. J. Med. Chem. 1993, 36, 2420-2423. 

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