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alpha,alpha-Difluoro-beta-aminodeoxystatine-containing renin inhibitory peptides
S Thaisrivongs1, H J Schostarez, D T Pals
1Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Journal of Medicinal Chemistry
|October 1, 1987
Summary
Researchers synthesized novel difluoroamino acid intermediates for enzyme inhibitors. These compounds, when incorporated into angiotensinogen analogues, demonstrated renin inhibition, though less potent than difluorostatine analogues.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Biochemistry
Background:
- Enzyme inhibitors are crucial for therapeutic interventions.
- Difluorinated amino acid analogues offer unique structural properties for drug design.
- Statine analogues are known for their potential in inhibiting aspartyl proteases like renin.
Purpose of the Study:
- To describe the preparation of novel sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates.
- To evaluate the utility of these compounds as synthetic intermediates for enzyme inhibitors.
- To assess the renin inhibitory activity of angiotensinogen analogues containing these novel difluorinated amino acid inserts.
Main Methods:
- Stereospecific intramolecular displacement via a Mitsunobu reaction.
- Synthesis of beta-lactam ring from beta-hydroxy hydroxamate precursors.
- Incorporation of novel diamino-difluoro-methylheptanoic acid inserts into angiotensinogen analogues.
Main Results:
- Successful preparation of sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates (7a and 7b).
- Angiotensinogen analogues VII and VIII containing these novel difluorinated amino acids were synthesized.
- These analogues demonstrated inhibition of the enzyme renin.
- Compounds containing alpha,alpha-difluoro-beta-aminodeoxystatine were weaker renin inhibitors compared to difluorostatine analogues.
Conclusions:
- The described synthetic route provides valuable intermediates for enzyme inhibitor development.
- Novel difluorinated amino acid analogues can be incorporated into peptide structures to modulate biological activity.
- While showing renin inhibitory activity, the alpha,alpha-difluoro-beta-aminodeoxystatine analogues were less potent than their difluorostatine counterparts, suggesting structure-activity relationships.