Benzothiazepine Compounds as ASBT Inhibitors for Metabolic Disorders
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Solution Overview
Problem
There is a need for additional bile acid modulating compounds with an optimized profile of potency, selectivity, and bioavailability to effectively inhibit bile acid circulation, which is desirable for treating various diseases.
Innovation Solution
The development of specific 1,5-benzothiazepine derivatives that act as potent inhibitors of the apical sodium-dependent bile acid transporter (ASBT) and/or liver bile acid transporter (LBAT), offering a range of structural variations to enhance therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing bile acid modulating compounds are used, then bile acid circulation can be inhibited, but the potency, selectivity, and bioavailability are not optimized
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical parameters of the benzothiazepine core structure, including substitutions at positions 3, 5, 7, and 8 with various functional groups (halogens, alkyl groups, aryl groups, heteroaryl groups). These structural parameter changes optimize the compounds' potency, selectivity, and bioavailability for inhibiting ASBT and LBAT transporters, resolving the contradiction between existing compound limitations and therapeutic efficacy requirements.
2Productivity
If bile acid reabsorption is inhibited, then lipid and glucose metabolism improve, but the need for compounds with optimized potency and selectivity remains
Solution Approach 1:
The patent applies local quality by introducing specific substituents at particular positions on the benzothiazepine core structure. For example, specific halogen atoms (fluoro, chloro, bromo) at defined positions, or specific alkyl groups (methyl, ethyl, propyl, butyl) provide localized modifications that enhance selectivity for ASBT/LBAT transporters while maintaining the overall metabolic improvement effect. This localized structural optimization resolves the contradiction between productivity and manufacturing precision.
Data Source
AI summary
The invention relates to 1,5-benzothiazepine derivatives of formula (I). 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.