Beta-Carboline SSTR3 Antagonists for Type 2 Diabetes

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Solution Overview

Problem

Current treatments for Type 2 diabetes, such as biguanides, glitazones, sulfonylureas, and DPP-4 inhibitors, have limitations including side effects and inefficiencies in managing hyperglycemia, insulin resistance, obesity, and lipid disorders, with a need for more effective and safer therapeutic options.

Innovation Solution

Development of bicyclic beta-carboline derivatives that act as selective antagonists of the somatostatin subtype receptor 3 (SSTR3), which can be used to increase insulin secretion in response to glucose and treat conditions like Type 2 diabetes, insulin resistance, obesity, and lipid disorders, either alone or in combination with other therapeutic agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional diabetes treatments (biguanides, glitazones, sulfonylureas, DPP-4 inhibitors) are used, then hyperglycemia and insulin resistance can be managed, but side effects and inefficiencies occur

Engineering Contradiction:

Improveeffectiveness in managing hyperglycemia and insulin resistanceVSAvoidside effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of beta-carboline derivatives by changing parameters such as substituting hydrogen atoms at specific positions (e.g., position 1 with electron-withdrawing groups like cyano or carbonyl groups), adjusting molecular weight, and modifying pharmacological properties to achieve selective SSTR3 antagonism with reduced side effects while maintaining therapeutic effectiveness

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces local functional groups at specific positions within the beta-carboline molecule (such as electron-withdrawing groups at position 1 and electron-donating groups at position 2) to create localized chemical properties that enhance SSTR3 receptor binding affinity and selectivity while minimizing interaction with other receptors that cause side effects

Inventive Principle:

Principle #3Local quality

2Reliability

If existing diabetes medications are administered, then glucose control is achieved, but safety profiles are compromised

Engineering Contradiction:

Improveglucose control effectivenessVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the potential harm of non-selective receptor activation into a benefit by designing beta-carboline derivatives that selectively target SSTR3 receptors, thereby achieving glucose control through a specific mechanism while avoiding the adverse effects associated with non-selective receptor binding

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The beta-carboline derivatives act as intermediary compounds that mediate between glucose sensing and insulin secretion by selectively blocking SSTR3 receptors, thereby improving safety profiles while maintaining effective glucose control through a controlled pharmacological pathway

Inventive Principle:

Principle #24Intermediary (Mediator)

3Quantity of substance

If beta-cell mass increases to compensate for insulin resistance, then insulin output increases, but beta-cell apoptosis occurs

Engineering Contradiction:

Improveinsulin outputVSAvoidbeta-cell survival

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent employs a feedback mechanism where selective SSTR3 antagonism by beta-carboline derivatives restores normal insulin secretion patterns in response to glucose levels, preventing the compensatory hyperinsulinemia that leads to beta-cell apoptosis while maintaining adequate insulin output

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS8754099B2Oxadiazole beta carboline derivatives as antidiabetic compounds

Publication Date: 2014.06.17 MERCK SHARP & DOHME LLC

AI summary

Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.