Selective Non-Cyclic Nucleotide EPAC1 Activators

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Solution Overview

Problem

Current EPAC agonists derived from cyclic nucleotides suffer from off-target side effects and poor pharmacokinetic profiles, limiting their potential for biological applications, and there is a need for potent and selective non-cyclic nucleotide small-molecule EPAC1 activators.

Innovation Solution

Development of novel non-cyclic nucleotide EPAC1 ligands, including compounds like PW0381, PW0521, PW0577, PW0606, PW0624, and PW0625, which selectively activate EPAC1 protein with improved stability and selectivity over related enzymes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If cyclic nucleotide-derived EPAC agonists are used, then EPAC activation is achieved, but off-target side effects and poor pharmacokinetic profiles occur

Engineering Contradiction:

ImproveEPAC activation reliabilityVSAvoidoff-target side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the fundamental chemical structure parameter from cyclic nucleotide to non-cyclic nucleotide scaffold, while maintaining the key functional feature of EPAC activation. This structural parameter change eliminates off-target effects and improves pharmacokinetic profiles while preserving the desired biological activity.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates simplified copies of the cyclic nucleotide structure that retain the essential EPAC-binding features without the problematic cyclic phosphate group. These copy structures (non-cyclic nucleotides) mimic the active conformation and key interactions with EPAC while removing the source of off-target effects.

Inventive Principle:

Principle #26Copying

2Reliability

If cyclic nucleotide-derived EPAC agonists are used, then EPAC activation is achieved, but poor pharmacokinetic profiles occur

Engineering Contradiction:

ImproveEPAC activation reliabilityVSAvoidpharmacokinetic stability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent modifies the chemical stability parameter by replacing the cyclic phosphate linkage with a non-cyclic structure, which confers greater metabolic stability and improved pharmacokinetic properties while maintaining sufficient potency for EPAC activation.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If non-cyclic nucleotide EPAC1 ligands are developed, then selectivity and stability are improved, but synthesis complexity increases

Engineering Contradiction:

ImproveEPAC1 selectivityVSAvoidsynthesis ease

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent divides the molecule into distinct functional segments (nucleotide base, sugar moiety, and tail region) that can be independently optimized and synthesized, then assembled through standardized coupling reactions, thereby managing synthesis complexity while achieving high selectivity.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20230150929A1Selective non-cyclic nucleotide activators for the camp sensor EPAC1

Publication Date: 2023.05.18 BOARD OF RGT THE UNIV OF TEXAS SYST

AI summary

The invention relates generally to novel EPAC1 activators, such as Formula I and II and the preparation thereof as well as the use of EPAC1 activators disclosed herein as to selectively activate EPAC1 in cells.