BK B2 Receptor Antagonists with Improved Metabolic Stability
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Solution Overview
Problem
Existing BK B2 receptor antagonists suffer from low metabolic stability, low bioavailability, and bioactivation leading to toxicity, limiting their utility as effective therapeutic agents for pathophysiological conditions associated with bradykinin levels.
Innovation Solution
Development of new BK B2 receptor antagonists according to general formula (I), which exhibit improved pharmacokinetic and physiochemical properties such as enhanced bioavailability, metabolic stability, and reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing BK B2 receptor antagonists are used, then bradykinin receptor blockade activity is achieved, but metabolic stability is low and bioavailability is poor
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of quinoline derivatives through varying substituents at specific positions (R1-R6, A1-A6, B1-B6) to optimize the balance between metabolic stability and bioavailability. The general formula (I) defines specific structural parameters that improve pharmacokinetic properties while maintaining B2 receptor antagonistic activity.
2Object-affected harmful factors
If existing BK B2 receptor antagonists are used, then receptor blockade activity is achieved, but bioactivation leads to toxicity
Solution Approach 1:
The patent converts the harmful bioactivation pathway into a beneficial outcome by designing molecules that undergo metabolic transformation into inactive metabolites rather than toxic species. The structural features in formula (I) are specifically chosen to direct metabolism toward non-toxic pathways while maintaining the desired pharmacological activity.
3Object-affected harmful factors
If existing BK B2 receptor antagonists are used, then therapeutic effect is achieved, but formation of glutathione adducts occurs
Solution Approach 1:
The patent extracts or removes the problematic reactive functional groups that lead to glutathione adduct formation by selecting specific substituent patterns in the general formula (I) that eliminate electrophilic centers prone to conjugation with glutathione, thereby preventing adduct formation while preserving metabolic stability.
Data Source
AI summary
The invention relates to a compound according to general formula (I), which acts as a bradykinin (BK) B2 receptor antagonist; to a pharmaceutical composition containing one or more of the compound(s) of the invention; to a combination preparation containing at least one compound of the invention and at least one further active pharmaceutical ingredient; and to said compound(s) for use as in a method of treating a skin disorder; eye disease; ear disease; mouth, throat and respiratory disease; gastrointestinal disease; liver, gallbladder and pancreatic disease; urinary tract and kidney disease; disease of male genitale organs and female genitale organs; disease of the hormone system; metabolic disease; cardiovascular disease; blood disease; lymphatic disease; disorder of the central nervous system; brain disorder; musculoskeletal system disease; allergy disorder; pain; infectious disease; inflammatory disorder; injury; immunology disorder; cancer; hereditary disease; or edema.