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.

Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists

Publisher Summary Pharmacological interruption of the renin-angiotensin system is a powerful tool for elucidating its role in hypertensive disease. This chapter discusses various approaches to the inhibition of different components of this system, but concentrates on the recent developments concerning those agents that have the greatest potential for therapeutic use. Renin is inhibited in vitro by high concentrations of naturally occurring renal lysophosphatidylethanolamines, synthetic phosphatidylethanolamines, and lysophosphatidylethanolamine analogs, and also by neutral lipids and phosphatidylcholine derivatives. In spite of their weak inhibitory activity in vitro, several of these compounds significantly lower blood pressure in the Goldblatt two-kidney renal hypertensive rat (RHR), a renin-mediated hypertensive model, in which one renal artery is constricted and the other kidney is left intact. Renin inhibitors have a unique potential for studying the pathophysiological function of the renin-angiotensin system, as they lack the ambiguity of angiotensin antagonists (partial agonism) or angiotensin-converting enzyme (ACE) inhibitors (bradykinin potentiation). However, none of the inhibitors of renin that have been developed till date has been thoroughly evaluated in vivo. Parenterally administered, AII antagonists and ACE inhibitors have contributed significantly to the understanding of the renin-angiotensin system and its role in human hypertension. The orally active ACE inhibitors show great promise as a novel type of antihypertensive drug.

Chapter 9. Inhibitors of the Renin-Angiotensin System

Two different structural types were proposed in 1977 (1) as leads for the development of nonpeptidic angiotensin-converting enzyme (ACE) inhibitors: mercaptoalkanoyl amino acids and carboxyalkanoyl amino acids.The development of the first structural type led to the identification of captopril, the first orally active ACE inhibitor to reach clinical application in hypertension and congestive heart failure. Elaboration of the second structural type by Patchett and collaborators led to the development of a new class of potent ACE inhibitors; carboxyalkyl dipeptides, and to the identification of enalapril, the second orally active ACE inhibitor to reach clinical application. Detailed structure-activity investigations (2, 3) indicate that both types of inhibitors bind to the active site in similar manner. The electrostatic interaction through the proline carboxyl, hydrogen bonding through the amide carbonyl, and the hydrophobic and/or entropic contributions of the five member ring of proline and the α-methyl g...

Angiotensin-Converting Enzyme Inhibitors: Accomplishments and Challenges

NOVEL PEPTIDFE AMIDES OF THE GENERAL FORMULA R-MET-GLY-TRP-MET-ASP-PHE-NH2 WHEREIN R REPRESENTS L-ASPARTYL-3''-SULFONYL-L-TYROSYL, L-ASPARTYL-L-ARGINYL-L-ASPARTYL-3''-SULFONYL-L-TYROSYL, OR ISOLEUCYL - L - SERYL-LASPARTYL-L-ARGINYL-L-ASPARTYL-3''SULFONYL-L-TYROSYL, AND INTERMEDIATES IN THE PRODUCTION THEREOF. THE PEPTIDE AMIDES OF THIS INVENTION AS WELL AS THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF HAVE BEEN FOUND TO POSSES CHOLECYSTOKININ ACTIVITY.

C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin (cck-pz)

Ester and amides of the nonapeptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro have been found to inhibit the hypertensive effect of angiotensin I.

Peptide enzyme inhibitors of angiotensin I

New substituted acyl derivatives of amino acids which have the general formula ##STR1## are useful as angiotensin converting enzyme inhibitors.

Miguel A. Ondetti

Papers

Chapter 9. Inhibitors of the Renin-Angiotensin System

Angiotensin-Converting Enzyme Inhibitors: Accomplishments and Challenges

C-sulfonated tyrosyl peptides related to cholecystokinin-pan-creozymin (cck-pz)

Peptide enzyme inhibitors of angiotensin I

Amino mercapto substituted acylamino acids