ABSTRACT
Conformationally constrained phenylbutyl(hydroxyphosphinyl)acyl dipeptides are potent inhibitors of angiotensin converting enzyme. The activity enhancement obtained by introducing conformational constraint into these molecules is greater than for related sulfhydryl and carboxyl analogs. The results are interpreted in terms of a binding model which optimally positions both zinc binding and hydrophobic groups for active site binding.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Dipeptides/chemical synthesis , Peptides, Cyclic/chemical synthesis , Angiotensin I/pharmacology , Animals , Blood Pressure/drug effects , Captopril/pharmacology , Indicators and Reagents , Kinetics , Magnetic Resonance Spectroscopy , Mass Spectrometry , Peptides, Cyclic/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The design rationale for a new series of tripeptide derived angiotensin converting enzyme (ACE) inhibitors, which we term "ketomethylureas", is described. Analogs of tripeptide substrates (i.e. N-benzoyl-Phe-Ala-Pro) in which the nitrogen atom of the scissile amide bond and the adjacent asymmetric carbon atom of the penultimate amino acid residue are formally transposed give rise to this novel class of inhibitors. The most potent ketomethylureas inhibit ACE with I50 values in the nM range.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Ketones/chemical synthesis , Methylurea Compounds/chemical synthesis , Animals , Indicators and Reagents , Ketones/pharmacology , Kinetics , Methylurea Compounds/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Modification of alanyl proline by introduction of both zinc coordinating and S1 subsite binding interactions affords potent new carboxy- and mercapto-acyl dipeptide angiotensin-converting enzyme (ACE) inhibitors. Design of these inhibitors was guided by an extension of the hypothetical ACE active site model originally used to derive captopril. Significant increases in ACE inhibitory activity were observed by introduction of conformation constraint into acyclic acyl dipeptides, thus further defining the three dimensional structure of the ACE active site.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Enzyme Inhibitors/analysis , Binding Sites , Dipeptides/analysis , Dipeptides/pharmacology , Models, Chemical , Protein Conformation , Structure-Activity Relationship , Zinc/metabolismABSTRACT
The design rationale for a new series of angiotensin-converting enzyme (ACE) inhibitors which incorporate a ketone substituent into a peptide backbone is described. Molecular regions which were expected to mimic the binding of an N-acyl tripeptide substrate at secondary binding sites S1 and S1' were systematically varied in order to study the specificity of inhibitor binding and optimize inhibition against ACE. The most effective ketomethyldipeptides inhibit ACE in the 10(-9) M range.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Dipeptides/pharmacology , Dipeptides/chemical synthesis , Protein Binding , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Results of an investigation aimed at identifying the consequences of chemical modifications of the alpha-aminoketone moiety of ketomethyldipeptides on angiotensin converting enzyme (ACE) inhibition are reported. These studies lead to the conclusion that within this series, the optimal structural backbone formulation for inhibition of ACE is represented by 1. Introduction of a Sar-Pro C-terminal dipeptide in this system, in contrast to other inhibitor classes, is compatible with potent inhibitory activity. Other structure-activity relationships for ketomethyldipeptides and related derivatives are presented, and speculations on possible modes of binding of these inhibitors to ACE, and on the question of ketone rehybridization are offered.