6-Substituted Naphthalene Derivatives Targeting Monomeric eNAMPT

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Solution Overview

Problem

Current compounds targeting extracellular nicotinamide phosphoribosyl transferase (eNAMPT) have limitations, including non-specificity across cell types, leading to a negligible therapeutic window, and existing treatments for conditions like cancer have not shown a usable therapeutic window, while monoclonal antibodies and small-molecule inhibitors face challenges in selectively suppressing proinflammatory effects without affecting intracellular NAMPT activity.

Innovation Solution

Development of compounds that selectively suppress the proinflammatory effects of monomeric extracellular NAMPT by stabilizing the protein in a dimeric form or inducing conformational changes, thereby minimizing inhibition of intracellular NAMPT activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If small-molecule NAMPT inhibitors are used to reduce cellular NAD+ levels, then proinflammatory effects are suppressed, but intracellular NAMPT activity is also inhibited leading to negligible therapeutic window

Engineering Contradiction:

Improveproinflammatory effectsVSAvoidinhibition of intracellular NAMPT activity

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The compound is designed to exhibit different functional properties at different locations: extracellularly it suppresses proinflammatory effects by blocking monomeric eNAMPT, while intracellularly it maintains NAMPT enzymatic activity for NAD+ synthesis. This spatial differentiation of function resolves the contradiction between suppressing harmful proinflammatory effects and avoiding harmful intracellular inhibition.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

Instead of directly inhibiting intracellular NAMPT activity to achieve therapeutic effect, the invention inverts the approach by targeting extracellular monomeric eNAMPT for suppression while preserving intracellular dimeric NAMPT function. This inverted strategy allows suppression of harmful effects without generating harmful intracellular inhibition.

Inventive Principle:

Principle #13The other way round (Inversion)

2Reliability

If compounds target extracellular NAMPT to suppress proinflammatory effects, then therapeutic benefit is achieved, but non-specificity across cell types reduces therapeutic window

Engineering Contradiction:

Improvetherapeutic benefitVSAvoidspecificity across cell types

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The compound achieves location-specific action by being selective for extracellular monomeric eNAMPT versus intracellular dimeric NAMPT. This local quality differentiation ensures reliable therapeutic benefit through specific extracellular targeting while adapting to different cell types by preserving their intracellular NAMPT function.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The invention exploits the conformational state parameter of NAMPT (monomeric vs dimeric) and location parameter (extracellular vs intracellular) to achieve specificity. By designing the compound to recognize and bind specifically to monomeric extracellular eNAMPT, it achieves both reliable therapeutic benefit and cell type adaptability.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If monoclonal antibodies block proinflammatory effects of eNAMPT, then beneficial effects are observed, but device complexity and manufacturing difficulty increase

Engineering Contradiction:

Improvebeneficial effectsVSAvoidcomplexity of monoclonal antibody therapy

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The invention replaces complex, expensive monoclonal antibodies with simpler, smaller molecule compounds that can be administered systemically. These small-molecule compounds achieve the same therapeutic benefit of blocking proinflammatory effects while being more suitable for routine clinical use with simpler manufacturing and administration protocols.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The invention substitutes the biological mechanism of monoclonal antibody-protein interaction with a chemically-based small-molecule ligand-receptor interaction. This substitution maintains the therapeutic effect of blocking eNAMPT proinflammatory activity while eliminating the complexity associated with producing and administering large protein-based therapeutics.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Data Source

PatentUS20240300968A16-substituted naphthalene-1,3-disulfonic acid derivatives as modulators of the extracellular nicotinamide phosphoribosyl transferase (enampt) for the treatment of e.g. diabetes

Publication Date: 2024.09.12 UNIV OF MANCHESTER

AI summary

This invention relates to therapeutic 6-substituted naphthalene-1,3-disulfonic acid derivatives of formula (I) (Formula (I)). More specifically, the invention relates to compounds of formula (I) useful as modulators of extracellular nicotinamide phosphoribosyl transferase (eNAMPT) that stabilize the protein in its dimeric form. In addition the invention contemplates pharmaceutical compositions comprising the compounds, processes to prepare the compounds and the compounds for use in methods of medical treatment of e.g. (i) diabetes; (ii) cardiovascular disease; (iii) inflammatory bowel condition; (iv) cancer; (v) liver disease; (vi) inflammatory skin conditions; (vii) lung conditions; (viii) arthritis; (ix) kidney disease (e.g. chronic kidney disease); or (x) sepsis. An exemplary compound is e.g. 6-(2-fluoro-5-((3-(4-(piperidin-1-ylsulfonyl) phenyl) ureido)methyl)phenyl)-4-(trioxidaneylthio) naphthalene-2-sulfonic acid (example 1).