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Renin inhibitor: relationship between molecular structure and oral absorption
N Hashimoto1, T Fujioka, K Hayashi
1Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Pharmaceutical Research
|October 1, 1994
Summary
Developing effective renin inhibitors involves enhancing solubility and oral absorption. This study shows that modifying molecular structure and using cyclodextrins (CD) can overcome these challenges, improving bioavailability.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Drug Delivery
Background:
- Developing renin inhibitors faces challenges including poor solubility, low oral absorption, and rapid hepatic clearance.
- Optimizing molecular structure is crucial for overcoming these pharmacokinetic limitations.
Purpose of the Study:
- To investigate strategies for improving the solubility, intestinal absorption, and oral bioavailability of renin inhibitors.
- To evaluate the role of molecular modifications and cyclodextrins in enhancing renin inhibitor pharmacokinetics.
Main Methods:
- Utilized cyclodextrins (CD), specifically beta-cyclodextrin (beta-CD), to enhance the solubility of renin inhibitors.
- Employed rat intestinal loop experiments to assess the intestinal absorption of renin inhibitors.
- Investigated the impact of N-terminal and C-terminal substitutions, including a naphthyl group, on absorption.
- Examined the effect of N-methylation on hepatic clearance and oral bioavailability.
Main Results:
- Beta-cyclodextrin significantly improved the solubility of renin inhibitors.
- Intestinal absorption was dependent on both solubility and molecular structure, with specific substitutions enhancing uptake.
- N-terminal modifications, particularly a naphthyl group, improved intestinal absorption.
- N-methylation of thiazolylalanine in compound 18 reduced hepatic clearance, leading to enhanced oral bioavailability.
Conclusions:
- Molecular structure modification and the use of beta-cyclodextrin are effective strategies to improve renin inhibitor solubility and intestinal absorption.
- Specific structural modifications, such as N-terminal substitutions and N-methylation, are essential for enhancing oral bioavailability by addressing absorption and clearance issues.
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