C-aryl glucoside SGLT2 inhibitor selectivity

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Solution Overview

Problem

Current treatments for type II diabetes lack selective inhibitors for SGLT2, leading to potential adverse effects on SGLT1, such as impaired glucose uptake and gastrointestinal issues, and general inhibitors fail to effectively manage plasma glucose levels without significant side effects.

Innovation Solution

Development of a C-aryl glucoside compound that selectively inhibits SGLT2, allowing for the enhancement of glucose excretion in the urine, thereby normalizing plasma glucose levels and delaying diabetic complications without significant gastrointestinal side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If general SGLT inhibitors are used to reduce plasma glucose levels, then glucose excretion is enhanced, but gastrointestinal side effects and impaired glucose uptake occur due to SGLT1 inhibition

Engineering Contradiction:

Improveplasma glucose levelsVSAvoidgastrointestinal side effects

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The invention segments the SGLT transporter system by developing a compound that selectively targets SGLT2 while sparing SGLT1. This segmentation allows independent control of renal glucose reabsorption (SGLT2) versus intestinal glucose uptake (SGLT1), resolving the contradiction between glucose lowering efficacy and gastrointestinal side effects

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The compound exhibits local quality differences in its inhibitory activity: high selectivity for SGLT2 in the kidney proximal tubule S1 segment, while showing minimal activity against SGLT1 in the intestine and distal S3 segment. This localized selectivity enables glucose excretion enhancement without compromising intestinal glucose absorption

Inventive Principle:

Principle #3Local quality

2Quantity of substance

If SGLT1 is inhibited to reduce plasma glucose, then glucose uptake in intestine is impaired, but this causes life-threatening diarrhea and dehydration

Engineering Contradiction:

Improveplasma glucose levelsVSAvoidsafety of glucose uptake

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The invention applies segmentation by selectively inhibiting only the SGLT2 segment while preserving SGLT1 function. This ensures that intestinal glucose uptake (SGLT1) remains intact, preventing the severe gastrointestinal side effects and dehydration associated with SGLT1 inhibition, while still achieving glucose lowering through SGLT2-mediated renal excretion

Inventive Principle:

Principle #1Segmentation

3Quantity of substance

If non-selective SGLT inhibitors are used, then plasma glucose levels are reduced, but adverse effects on renal function and ion balance occur

Engineering Contradiction:

Improveplasma glucose levelsVSAvoidrenal function adverse effects

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

The compound demonstrates local quality selectivity by preferentially binding to and inhibiting SGLT2 in the kidney proximal tubule S1 segment, while having minimal effect on SGLT1 and other renal transporters. This localized selectivity reduces off-target effects on renal function and ion balance, maintaining safety while achieving glucose lowering efficacy

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS7589193B2C-aryl glucoside SGLT2 inhibitors and method

Publication Date: 2009.09.15 BRISTOL MYERS SQUIBB CO

AI summary

A compound of the formula IA method is also provided for treating diabetes and related diseases employing the above compound alone or in combination with another therapeutic agent.