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Renin inhibitory pentols showing improved enteral bioavailability
H W Kleemann1, H Heitsch, R Henning
1Hoechst AG, Frankfurt/M, Germany.
Journal of Medicinal Chemistry
|February 7, 1992
Summary
New hydrophilic renin inhibitors, designed with a C-terminal pentahydroxy group, show potential for treating hypertension. These low molecular weight compounds are easily synthesized and demonstrate effective hypotensive effects in animal models.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Cardiovascular Research
Background:
- Renin inhibitors are crucial for managing hypertension.
- Developing orally bioavailable and potent inhibitors remains a challenge.
- Traditional renin inhibitors often require complex synthesis and lack sufficient water solubility.
Purpose of the Study:
- To synthesize and characterize novel, low molecular weight, hydrophilic renin inhibitors.
- To evaluate the pharmacokinetic properties and in vivo efficacy of these inhibitors.
- To assess the potential of these compounds as therapeutic agents for hypertension.
Main Methods:
- Chemical synthesis of C-terminal pentahydroxy functionalized renin inhibitors.
- Assessment of compound transport across rabbit intestinal brush border membrane vesicles.
- Evaluation of hypotensive effects in sodium-depleted rhesus monkeys following oral dosing.
Main Results:
- Novel potent, low molecular weight hydrophilic renin inhibitors were successfully synthesized.
- Compound 33 demonstrated transport across intestinal membrane vesicles, indicating potential oral absorption.
- Compound 33 induced a significant and sustained hypotensive effect in rhesus monkeys at a low dose.
Conclusions:
- The C-terminal pentahydroxy modification yields effective, orally absorbable renin inhibitors.
- These novel inhibitors represent a promising new class of antihypertensive agents.
- Further development of these hydrophilic renin inhibitors is warranted for clinical application.