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Biomedical subjects

M A Ondetti

Publications and source records attributed to M A Ondetti.

At least 19 recordsLinked to original sources
PubMed1988

Structural relationships of angiotensin converting-enzyme inhibitors to pharmacologic activity.

The angiotensin converting-enzyme inhibitors available so far are active-site directed inhibitors. They utilize all the critical binding interactions of the substrate and convert the catalytic interaction with the zinc atom into an effective binding interaction. Three chemical classes of angiotensin converting-enzyme inhibitors have been introduced into clinical use, the sulfhydryl-containing inhibitors such as captopril and its analogs and prodrugs, carboxyalkyldipeptides such as enalapril and its analogs, and phosphorus-containing inhibitors such as fosinopril and the phosphonate SQ 29,852. Within each of the three groups of inhibitors significant differences in molecular weight and polarities can be observed. These differences have a significant influence in the routes of elmination and tissue distribution of these inhibitors. Tissue distribution and intrinsic potency will determine the magnitude of angiotensin converting-enzyme inhibition at the tissue level, which could play a critical role in the clinical utilization of these inhibitors. The sulfhydryl-containing inhibitors such as captopril undergo a metabolic process significantly different from that of the other two classes. They can interact with endogenous sulfhydryl-containing compounds like glutathione and proteins, to form reversible disulfides, which can serve as depot forms of the drug. Also, because of their redox properties they might function as recyclable free radical scavengers.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Rational design and biochemical utility of specific inhibitors of angiotensin-converting enzyme.

Angiotensin-converting enzyme (ACE), the receptor for an important new class of antihypertensive drugs, is now one of the better studied zinc metallopeptidases. The development of several classes of tightly binding competitive inhibitors of ACE has led to increased understanding of the structure and function of this enzyme while also yielding important new drugs for the diagnosis and treatment of hypertensive disease. Peptides from snake venom provided the first proof of the therapeutic utility of ACE inhibitors, and a tripeptide sequence, Phe-Ala-Pro, was used as a model for sidechain interactions with ACE in the rational design of simpler nonpeptidic inhibitors such as captopril and enalapril. These and more recently developed ACE inhibitors can be classified according to their structural analogy to dipeptides or tripeptides and according to the nature of their zinc-binding ligands, such as sulfhydryl, ketone, carboxylate, or hydroxyphosphinyl, that contribute greatly to their binding to ACE. Several newer ACE inhibitors have increased potency and/or improved pharmacokinetic properties due to modifications such as substitution of the proline ring or replacement of the methyl side chain analogous to Ala by an aminobutyl residue analogous to Lys. The availability of structurally diverse ACE inhibitors with great potency and specificity provides a powerful biochemical tool for purification, localization, and characterization of ACE in different tissues, and for distinguishing related zinc metallopeptidases with similar properties.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1984

Angiotensin-converting enzyme inhibitors: biochemical properties and biological actions.

The review will cover the chemistry and biochemistry of angiotensin-converting enzyme inhibitors with emphasis on data published since the publication of previous reviews. The relative merits of each contribution will be evaluated, as well as their potential for leading to new discoveries. The biology of angiotensin-converting enzyme inhibitors will be brought up-to-date to give the reader an appreciation of the medical implications of this new type of antihypertensive agent.

Angiotensin II↗
PubMed1982

Development and design of specific inhibitors of angiotensin-converting enzyme.

Captopril is a remarkably effective new antihypertensive drug designed and developed as a potent and specific inhibitor of angiotensin-converting enzyme, a zinc metallopeptidase that participates in the synthesis of a hypertensive peptide, angiotensin II, and in the degradation of a hypotensive peptide, bradykinin. Earlier studies with a snake venom peptide (teprotride or SQ 20881) that could be administered only by injection demonstrated that specific inhibitors of angiotensin-converting enzyme could be highly effective as antihypertensive drugs, and helped to clarify the specificity and mechanism of action of the enzyme. A hypothetical model of the active center of angiotensin-converting enzyme based on its presumed analogy to the well characterized zinc metallopeptidase carboxypeptidase A was used to guide logical sequential improvements of a weakly active prototype inhibitor that led eventually to the highly optimized structure of captopril. The hypothetical working model of the active site of angiotensin-converting enzyme used to develop captopril continues to provide a firm basis for development of new types of specific inhibitors of this biologically important enzyme.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1982

Angiotensin-converting enzyme inhibitors: importance of the amide carbonyl of mercaptoacyl amino acids for hydrogen bonding to the enzyme.

A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.

Amino Acids, Sulfur↗
PubMed1981

Chemical modifications of the active site of Streptomyces R61 DD-carboxypeptidase.

The DD-carboxypeptidase of Streptomyces R61 is an exocellular enzyme related to the bacterial peptidoglycan cross-linking enzymes, and, like them, is inhibited by penicillin. The active-site reagents methanesulfonyl fluoride and diisopropylfluorophosphate inhibit catalytic activity and binding of penicillin G indicating the involvement of a serine residue in both processes. For methanesulfonyl fluoride the second-order rate constant (0.7 M-1 min-1) is comparable to that of classical serine proteases. For diisopropylfluorophosphate, which binds to the enzyme stoichiometrically, the second-order rate constant (1.5 M-1 min-1) is at least two orders of magnitude smaller. The arginine-specific reagents methylglyoxal, 2,3-butanedione and phenylglyoxal inactive DD-carboxypeptidase in borate buffer with second-order rate constants of 70, 70 and 120 M-1 min-1, respectively. Inactivation correlates with stoichiometric binding to the enzyme. Peptidase and esterase activities are similarly affected, suggesting that substrate binding in both cases requires an arginine-carboxyl group interaction. Penicillin binding is also inhibited, but the degree of inhibition depends on the alpha-dicarbonyl side chain. Binding of alpha-dicarbonyls to DD-carboxypeptidase facilitates subsequent binding of diisopropylfluorophosphate suggesting that interaction of these compounds with the active site might induce a conformational change on the enzyme making the serine residue more accessible to the modifying reagent.

Binding Sites↗