Pyrazole Derivatives Inhibit SGLT1 to Control Postprandial Hyperglycemia
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Solution Overview
Problem
Current antidiabetic agents are inadequate in effectively inhibiting carbohydrate absorption in the small intestine, particularly for managing postprandial hyperglycemia and diabetes, as they do not significantly impact elevated glucose levels from monosaccharides and have limited activity range.
Innovation Solution
Development of pyrazole derivatives that exhibit inhibitory activity against human SGLT1, preventing carbohydrate absorption in the small intestine, thereby controlling blood glucose levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If α-glucosidase inhibitors are used to delay carbohydrate digestion and absorption, then postprandial hyperglycemia is improved, but they do not affect elevated glucose levels from monosaccharides and have limited activity range
Solution Approach 1:
The patent develops pyrazole derivative compounds that function as dual inhibitors of both α-glucosidase and SGLT1 transporters. This multi-functional approach allows the single compound to address both disaccharide digestion (via α-glucosidase inhibition) and monosaccharide absorption (via SGLT1 inhibition), thereby achieving broader activity range while maintaining effectiveness against monosaccharides
2Reliability
If SGLT1 activity is blocked to inhibit carbohydrate absorption, then blood sugar level increase is prevented, but new drug development is required to achieve potent inhibitory activity
Solution Approach 1:
The patent merges the pharmacophore structures of known α-glucosidase inhibitors with SGLT1 inhibitory moieties to create hybrid pyrazole derivative compounds. This structural merging approach allows the new compounds to simultaneously inhibit both enzyme and transporter, achieving potent SGLT1 inhibitory activity while building upon existing drug development knowledge and frameworks
Data Source
AI summary
The present invention provides pyrazole derivatives represented by the general formula:wherein R1 represents H, an optionally substituted C1-6 alkyl group etc.; one of Q and T represents a group represented by the general formula:or a group represented by the general formula:while the other represents an optionally substituted C1-6 alkyl group etc.; R2 represents H, a halogen atom, OH, an optionally substituted C1-6 alkyl group etc.; X represents a single bond, O or S; Y represents an optionally substituted C1-6 alkylene group etc.; Z represents —RB, —CORC etc. in which RB represents an optionally substituted C1-6 alkyl group etc.; and RC represents an optionally substituted C1-6 alkyl group etc.; R4 represents H, an optionally substituted C1-6 alkyl group etc.; and R3, R5 and R6 represent H, a halogen atom etc., pharmaceutically acceptable salts thereof or prodrugs thereof, which exhibit an excellent inhibitory activity in human SGLT1 and are useful as agents for the prevention or treatment of a disease associated with hyperglycemia such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications or obesity, and a disease associated with the increase of blood galactose level such as galactosemia, and pharmaceutical compositions comprising the same, pharmaceutical uses thereof, and intermediates for production thereof.