CGRP Receptor Antagonists Bypassing Hepatic First-Pass Metabolism
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Solution Overview
Problem
Current CGRP receptor antagonists for migraine treatment often require frequent administration and are associated with liver toxicity, limiting their clinical use, and there is a need for new compounds that do not induce liver injury.
Innovation Solution
Development of novel compounds with high affinity and potency as CGRP receptor antagonists for sub-cutaneous, intravenous, and intranasal routes of administration, which differ from oral molecules in molecular profile, to minimize liver burden and avoid first-pass exposure.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If oral CGRP receptor antagonists are used for migraine treatment, then the drug can be administered orally, but liver toxicity occurs and frequent administration is required
Solution Approach 1:
The patent extracts the problematic first-pass liver metabolism pathway by switching from oral to parenteral administration routes (subcutaneous, intravenous, or intranasal). This removes the harmful factor (liver toxicity) while maintaining the beneficial function (migraine treatment) through alternative delivery mechanisms that bypass hepatic first-pass metabolism.
Solution Approach 2:
The patent changes the administration parameter from oral to parenteral routes, fundamentally altering how the drug enters the system. This parameter change eliminates the harmful liver metabolism while maintaining therapeutic efficacy, as demonstrated by the compounds achieving high affinity and potency through non-orital pathways.
2Ease of operation
If oral CGRP receptor antagonists are used, then the drug can be taken orally, but frequent administration is required reducing productivity
Solution Approach 1:
The patent changes the administration route parameter from oral to parenteral, which fundamentally alters the pharmacokinetic profile. This enables longer duration of action and reduced administration frequency, improving productivity while maintaining ease of operation through simple injection or nasal administration.
3Object-affected harmful factors
If novel compounds are developed for non-orital routes, then liver toxicity is avoided, but the molecular profile must differ from oral molecules
Solution Approach 1:
The patent applies parameter changes to the molecular structure itself, creating compounds with different physicochemical properties suited for parenteral administration. These structural modifications enable the drugs to achieve high affinity and potency while bypassing hepatic metabolism, resolving the contradiction between avoiding liver toxicity and maintaining effective molecular design.
Data Source
AI summary
The disclosures herein relate to novel compounds of formulawherein R1, R2, R3 and R4 are as defined herein, and their use in treating, preventing, ameliorating, controlling or reducing cerebrovascular or vascular disorders associated with CGRP receptor function.