Pyrimidine DPP-4 Inhibitors Block GLP-1 Degradation

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Solution Overview

Problem

Current treatments for diabetes, particularly type II diabetes, face challenges due to the rapid degradation of GLP-1(7-36) by DPP-4, leading to short efficacy and the need for continuous infusion, and existing inhibitors have limitations in effectively managing diabetic complications.

Innovation Solution

Development of pyrimidine-based compounds that act as DPP-4 inhibitors, potentially administered alone or in combination with other therapeutic agents, to enhance endogenous GLP-1(7-36) levels and mitigate its antagonist GLP-1(9-36), thereby addressing diabetes and its complications.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If exogenous GLP-1(7-36) is administered continuously to maintain therapeutic levels, then diabetes treatment efficacy is improved, but treatment complexity and cost increase due to continuous infusion requirement

Engineering Contradiction:

Improvediabetes treatment efficacyVSAvoidcontinuous infusion requirement

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

DPP-4 inhibitors act as intermediary substances that block the degradation pathway of GLP-1(7-36). By inhibiting the DPP-4 enzyme, these compounds prevent the breakdown of endogenous GLP-1(7-36), thereby extending its half-life and maintaining therapeutic levels without requiring continuous external administration.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention enables the body's own GLP-1(7-36) hormone to serve its therapeutic function for an extended period. By protecting endogenous GLP-1(7-36) from rapid degradation through DPP-4 inhibition, the system allows the natural hormone to continue exerting its glucose-lowering effects without needing continuous external supplementation.

Inventive Principle:

Principle #25Self-service

2Stability of the object's composition

If DPP-4 activity is allowed to proceed normally, then metabolic pathways remain natural, but GLP-1(7-36) is rapidly degraded to its antagonist form GLP-1(9-36), reducing therapeutic benefit

Engineering Contradiction:

ImproveGLP-1(7-36) stabilityVSAvoidformation of GLP-1(9-36) antagonist

Core Design Contradiction:

Stability of the object's compositionVSObject-generated harmful factors

Solution Approach 1:

DPP-4 inhibitors are administered to preemptively block the enzyme's activity before GLP-1(7-36) can be degraded. This preliminary inhibition prevents the formation of the antagonist GLP-1(9-36) and maintains the stability and activity of the therapeutic GLP-1(7-36) form throughout its circulation.

Inventive Principle:

Principle #9Preliminary anti-action

3Reliability

If existing DPP-4 inhibitors are used, then some degree of GLP-1(7-36) protection is achieved, but diabetic complications such as retinopathy, neuropathy, and nephropathy are not effectively managed

Engineering Contradiction:

ImproveGLP-1(7-36) protectionVSAvoideffectiveness against diabetic complications

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the chemical structure of DPP-4 inhibitors by introducing specific pyrimidine-based scaffolds with varied substituents (R1, R2, R3, R4, R5, R6). These structural parameter changes enhance both the potency of GLP-1(7-36) protection and the compounds' ability to address multiple diabetic complications through improved pharmacokinetic and pharmacodynamic properties.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS7589088B2Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods

Publication Date: 2009.09.15 BRISTOL MYERS SQUIBB CO

AI summary

Compounds are provided having the formula (I)wherein R, B, X and Y are as defined herein.