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Dual angiotensin converting enzyme/thromboxane synthase inhibitors
G M Ksander1, M Erion, A M Yuan
1Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
Journal of Medicinal Chemistry
|June 10, 1994
Summary
Researchers developed dual angiotensin converting enzyme (ACE)/thromboxane synthase (TxS) inhibitors for superior hypertension treatment. These compounds showed potent blood pressure lowering in rats, with one combination nearly doubling the effect of a standard ACE inhibitor.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Medicinal Chemistry
Background:
- Hypertension remains a leading cause of cardiovascular disease.
- Current treatments like ACE inhibitors are effective but can be improved.
- Exploring dual-action inhibitors offers a novel therapeutic strategy.
Purpose of the Study:
- To synthesize and evaluate novel compounds with dual angiotensin converting enzyme (ACE) and thromboxane synthase (TxS) inhibitory activity.
- To investigate the antihypertensive efficacy of these dual inhibitors in spontaneously hypertensive rats (SHR).
- To determine if combined ACE and TxS inhibition offers superior blood pressure reduction compared to ACE inhibition alone.
Main Methods:
- Synthesis of novel chemical entities designed for dual ACE/TxS inhibition.
- In vitro assessment of inhibitory activity against ACE and TxS.
- Oral administration of candidate compounds (e.g., 8b, 11) and enalapril in SHR models.
- Measurement of blood pressure and pressor responses over a 24-hour period.
Main Results:
- Five series of compounds demonstrated potent in vitro dual ACE and TxS inhibition.
- Compounds 8b and 11 exhibited significant blood pressure lowering in SHR after oral administration.
- No direct correlation was observed between blood pressure reduction and A1 pressor response inhibition.
- Concurrent administration of enalapril with TxS inhibitor 3 nearly doubled the blood pressure-lowering effect over 24 hours.
Conclusions:
- Dual ACE/TxS inhibition is achievable within a single molecule.
- Novel dual inhibitors show promise for managing hypertension.
- Combination therapy with an ACE inhibitor and a TxS inhibitor significantly potentiates antihypertensive effects.