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alpha-Hydroxy phosphinyl-based inhibitors of human renin
D V Patel1, K Rielly-Gauvin, D E Ryono
1Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Journal of Medicinal Chemistry
|October 27, 1995
Summary
New alpha-hydroxy phosphonates are potent inhibitors of the aspartyl protease renin. These transition state analogs show promise for developing novel renin inhibitors, with one compound demonstrating significant in vivo activity.
Area of Science:
- Medicinal Chemistry
- Enzyme Inhibition
- Drug Discovery
Background:
- Aspartyl protease renin is a key target for managing hypertension.
- Developing potent and selective renin inhibitors is crucial for cardiovascular therapeutics.
- Transition state analogs offer a promising strategy for enzyme inhibition.
Purpose of the Study:
- To design and evaluate alpha-hydroxy phosphonates as novel inhibitors of human renin.
- To explore structure-activity relationships for optimizing inhibitor potency.
- To assess the in vivo efficacy and pharmacokinetic properties of lead compounds.
Main Methods:
- Synthesis of alpha-hydroxy phosphonate, phosphinate, and phosphine oxide analogs.
- In vitro enzyme inhibition assays to determine IC50 values against human renin.
- In vivo studies in conscious cynomolgus monkeys to evaluate renin inhibition and blood pressure effects.
Main Results:
- Alpha-hydroxy phosphonates were identified as potent inhibitors of human renin (IC50 values as low as 16 nM).
- The presence of at least one alkoxy group on phosphorus was essential for high activity.
- Inhibitors with leucine at the P2 position exhibited superior in vitro activity compared to histidine analogs.
- Compound 34 demonstrated complete and sustained plasma renin inhibition and reduced mean arterial pressure in vivo.
Conclusions:
- Alpha-hydroxy phosphonates represent a novel and promising class of transition state analog inhibitors of renin.
- These compounds hold potential for the development of new antihypertensive agents.
- Further structure-activity relationship studies can refine inhibitor design for enhanced therapeutic profiles.