A hypothetical model of the active site of angiotensin-converting enzyme, based on known chemical and kinetic properties of the enzyme, has enabled us to design a new class of potent and specific inhibitors. These compounds, carboxyalkanoyl and mercaptoalkanoyl derivatives of proline, inhibit the contractile response of guinea pig ileal strip to angiotensin I and augment its response to bradykinin. When administered orally to rats, these agents inhibit the pressor effect of angiotensin I, augment the vasodepressor effect of bradykinin, and lower blood pressure in a model of renovascular hypertension.

https://science.sciencemag.org/content/sci/196/4288/441.full.pdf

Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents

https://digital.csic.es/bitstream/10261/63157/4/Gomez-Guillen-collagenreview_CSIC.pdf

Functional and bioactive properties of collagen and gelatin from alternative sources: A review

The influence of natural products upon drug discovery.

Renin-angiotensin system: biochemistry and mechanisms of action.

3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.

Miguel A. Ondetti

Papers

Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents

Design of potent competitive inhibitors of angiotensin-converting enzyme. Carboxyalkanoyl and mercaptoalkanoyl amino acids.

Binding of peptide substrates and inhibitors of angiotensin-converting enzyme. Importance of the COOH-terminal dipeptide sequence.

Angiotensin-converting enzyme inhibitors from the venom of Bothrops jararaca. Isolation, elucidation of structure, and synthesis.

Enzymes of the Renin-Angiotensin System and their Inhibitors