Aminopyridine ALK-2 Inhibitors for Selective BMP Signaling Control

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Solution Overview

Problem

There is a need for alternative ways to regulate BMP signaling, particularly through the development of selective ALK-2 inhibitors to treat conditions such as fibrodysplasia ossificans progressiva (FOP) and non-hereditary heterotopic ossification (HO), as existing inhibitors may not be optimal in terms of selectivity, stability, and formulation.

Innovation Solution

Development of aminopyridine derivatives that act as selective ALK-2 inhibitors, demonstrating favorable pharmacokinetic properties, non-toxicity, and ease of formulation, with specific compounds like 2-amino-N-(4-hydroxycyclohexyl)-5-(4-(3-(1-(methylsulfonyl)piperidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)nicotinamide and others, which inhibit ALK-2 receptor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing BMP signaling inhibitors are used, then BMP signaling can be regulated, but selectivity and stability are insufficient

Engineering Contradiction:

ImproveselectivityVSAvoidinhibitor performance

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies chemical parameters of inhibitor molecules by introducing specific substituents (amminopyridine derivatives with various R1-R6 groups) to optimize the balance between selectivity for ALK-2 receptor and overall inhibitor performance, achieving improved reliability without sacrificing versatility

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite chemical structures combining multiple functional groups (amminopyridine core with various heterocyclic and aromatic substituents) to achieve both high selectivity for ALK-2 and improved stability, resolving the contradiction between reliability and adaptability

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If ALK-2 inhibitor compounds are developed, then heterotopic ossification can be reduced, but formulation stability and ease of formulation remain challenging

Engineering Contradiction:

Improveheterotopic ossificationVSAvoidformulation ease

Core Design Contradiction:

Object-affected harmful factorsVSEase of manufacture

Solution Approach 1:

The patent optimizes physical and chemical parameters of the inhibitor compounds (solubility, stability, molecular structure) to improve both their therapeutic efficacy in reducing heterotopic ossification and their ease of formulation, allowing effective dosing while simplifying manufacturing processes

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If selective ALK-2 inhibitors are administered, then FOP and HO can be treated, but side effects and toxicity must be minimized

Engineering Contradiction:

Improvedisease symptomsVSAvoidside effects

Core Design Contradiction:

Object-affected harmful factorsVSObject-generated harmful factors

Solution Approach 1:

The patent designs inhibitors with specific local chemical properties (amminopyridine core structure with targeted substituents) that enable selective binding to ALK-2 receptor, treating FOP and HO symptoms while minimizing off-target effects and toxicity through precise molecular localization of pharmacological activity

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS12466808B2Aminopyridine derivatives and their use as selective ALK-2 inhibitors

Publication Date: 2025.11.11 NOVARTIS AG

AI summary

The invention relates to a compound of formula (1) in free form or in pharmaceutically acceptable salt formto pharmaceutical compositions comprising said compound and to the use of said compound in the treatment of heterotopic ossification and fibrodysplasia ossificans progressiva.