Benzothiazepine Derivatives as ASBT Inhibitors
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Solution Overview
Problem
Current ASBT inhibitor compounds lack an optimized profile in terms of potency, selectivity, and bioavailability for effectively treating diseases related to bile acid circulation.
Innovation Solution
Development of specific 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives that act as potent inhibitors of the apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transporter (LBAT), offering a therapeutic option for conditions such as cardiovascular diseases, fatty acid metabolism disorders, gastrointestinal diseases, and liver diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current ASBT inhibitor compounds are used, then bile acid reabsorption is inhibited, but potency, selectivity, and bioavailability are insufficient
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures of ASBT inhibitor compounds, specifically altering substituents at positions 3, 5, 7, and 8 of the benzothiazepine ring system. This includes varying R1-R6 groups to optimize potency, selectivity, and bioavailability parameters, thereby resolving the contradiction between therapeutic effectiveness and potency profile
Solution Approach 2:
The patent employs composite materials by creating hybrid molecular structures that combine benzothiazepine cores with diverse substituent groups (aromatic rings, heterocycles, alkyl chains). These composite structures achieve enhanced potency and selectivity while maintaining therapeutic effectiveness, addressing the insufficiency of current single-structure inhibitors
2Power
If ASBT inhibition is increased to improve treatment efficacy, then bile acid circulation modulation is enhanced, but bioavailability and selectivity are compromised
Solution Approach 1:
The patent applies local quality by introducing specific functional groups at particular positions (R1 at position 3, R2 at position 5, R3 at position 7, R4 at position 8) of the benzothiazepine core. Each substituent is optimized independently to enhance local interactions with ASBT binding sites while maintaining overall molecular bioavailability, thus resolving the contradiction between inhibitory power and ease of operation
3Ease of manufacture
If compound structure is simplified for easier synthesis, then manufacturing is easier, but potency and therapeutic profile are reduced
Solution Approach 1:
The patent applies segmentation by dividing the complex inhibitor molecule into modular components: a core benzothiazepine structure (positions 1-8) and interchangeable substituent groups (R1-R6). This modular approach allows systematic optimization of potency through substituent variation while maintaining a consistent, synthesizable core structure, resolving the contradiction between ease of manufacture and manufacturing precision
Data Source
AI summary
The invention relates to certain 1,5-benzothiazepine and 1,2,5-benzothiadiazepine derivatives as defined herein. These compounds are bile acid modulators having apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transport (LBAT) inhibitory activity. The invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of cardiovascular diseases, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and liver diseases.