Tyk2 Prodrug Design for Solubility and Bioavailability Control

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Solution Overview

Problem

There is a need for improved delivery of compounds that modulate IL-12, IL-23, and/or IFNα to treat autoimmune and inflammatory diseases, with existing compounds facing challenges in solubility, dosage range, and pharmaceutical formulation.

Innovation Solution

Development of prodrugs of Compounds (I) and (II) that enhance solubility, stability, bioavailability, and therapeutic index, allowing for a wider dosage range and broader pharmaceutical formulations.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If prodrugs are developed to improve solubility and bioavailability, then therapeutic benefits are enhanced, but compound structure complexity increases

Engineering Contradiction:

Improvetherapeutic benefitsVSAvoidcompound structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

A prodrug moiety is introduced as an intermediary component that temporarily modifies the compound structure to improve solubility and bioavailability. This intermediary is designed to be cleaved in vivo, releasing the active parent compound while providing the desired pharmacokinetic benefits during the transit and distribution phase.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The compound structure is modified by changing physical-chemical parameters such as polarity, molecular weight, and functional groups through prodrug design. These parameter changes enhance aqueous solubility and membrane permeability without fundamentally altering the core pharmacophore, allowing the compound to meet therapeutic requirements while maintaining structural manageability.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If a wider dosage range is enabled through prodrug design, then treatment flexibility improves, but formulation complexity increases

Engineering Contradiction:

Improvedosage rangeVSAvoidpharmaceutical formulation

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The prodrug formulation is designed to serve multiple functions simultaneously: it provides solubility enhancement, enables a broader dosage range, improves stability, and facilitates various routes of administration. This multi-functional design allows a single formulation to adapt to different therapeutic needs and patient requirements without requiring multiple specialized formulations.

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Reliability

If solubility is improved through prodrug modification, then bioavailability increases, but synthesis complexity increases

Engineering Contradiction:

ImprovebioavailabilityVSAvoidsynthesis process

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The prodrug moiety is pre-attached to the parent compound during synthesis to improve solubility for subsequent formulation and administration steps. This preliminary modification is strategically designed to be introduced through a single, high-yielding chemical reaction that does not require complex multi-step synthesis, thereby maintaining ease of manufacture while achieving the desired solubility improvement for better bioavailability.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS12528782B2Prodrugs in the modulation of interleukin

Publication Date: 2026.01.20 BRISTOL MYERS SQUIBB CO

AI summary

There are disclosed prodrugs of the compounds of the formula. The prodrugs are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.