Selective ACE C-Domain Inhibitor for Reduced Side Effects
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Solution Overview
Problem
Current ACE inhibitors for hypertension and cardiovascular diseases often cause undesirable side effects such as persistent cough, loss of taste, and angioedema due to non-selective inhibition of angiotensin I and bradykinin, necessitating the development of domain-selective inhibitors that can effectively control blood pressure with reduced vasodilator-related side effects.
Innovation Solution
The development of N 2-(S)-(1-Carbonyl-3-phenylpropyl)-L-lysyl-L-tryptophan hydrochloride, a compound that selectively inhibits the C-domain of angiotensin-converting enzyme (ACE), allowing for more controlled blood pressure regulation and reduced side effects by maintaining some bradykinin degradation and altering the ratio of vasopressor to vasodilator peptides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stress or pressure
If non-selective ACE inhibitors are used to control blood pressure, then blood pressure regulation is achieved, but vasodilator-related side effects such as persistent cough, loss of taste, and angioedema occur
Solution Approach 1:
The ACE enzyme is divided into two functional domains: an N-domain that hydrolyzes bradykinin and a C-domain that converts angiotensin I to angiotensin II. The patent applies segmentation by designing inhibitors that selectively target one domain over the other, thereby achieving blood pressure control through C-domain inhibition while preserving bradykinin degradation through N-domain activity, thus reducing vasodilator-related side effects
Solution Approach 2:
The patent applies local quality by creating domain-selective inhibitors with specific molecular structures that preferentially bind to either the N-domain or C-domain of ACE. The compound N2-(S)-(1-Carbonyl-3-phenylpropyl)-L-lysyl-L-tryptophan hydrochloride is designed to selectively inhibit the C-domain, allowing localized inhibition at the blood pressure regulation site while leaving the bradykinin degradation pathway intact
2Object-affected harmful factors
If C-domain selective inhibitors are developed to reduce side effects, then vasodilator-related side effects are reduced, but the complexity of inhibitor design increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of ACE inhibitors, such as introducing specific amino acid residues at particular positions in the peptide sequence. The compound N2-(S)-(1-Carbonyl-3-phenylpropyl)-L-lysyl-L-tryptophan hydrochloride features specific parameter modifications (the S-configuration at the stereogenic center, the carbonyl group at position 1, and the phenylpropyl side chain) that collectively achieve C-domain selectivity while managing design complexity through structured chemical modification
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This compound achieves effective blood pressure control with reduced vasodilator-related side effects by selectively inhibiting the C-domain of ACE, potentially offering a safer therapeutic option for hypertension and cardiovascular diseases compared to existing mixed inhibitors.
Implementation Method 1
The development of N2-(S)-(1-Carbonyl-3-phenylpropyl)-L-lysyl-L-tryptophan hydrochloride, a compound that selectively inhibits the C-domain of angiotensin-converting enzyme (ACE)
Implementation Method 2
allowing for more controlled blood pressure regulation and reduced side effects by maintaining some bradykinin degradation
Data Source
AI summary
This invention relates to a process for synthesising an amino acid derivative of a tripeptidomimetic, such as lisinopril. The invention also relates to a derivative of lisinopril,incorporating a amino acid moeity such as tryptophan at the P2' position.