HSD17b13 inhibitors

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Solution Overview

Problem

Current treatments for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) lack potent and selective inhibitors of the HSD17B13 enzyme, which is associated with lipid metabolism and liver diseases.

Innovation Solution

Development of heteroaryl substituted 2,6-difluorophenol compounds that act as selective inhibitors of HSD17B13, modulating lipogenesis and potentially treating metabolic disorders, liver diseases, and cardiovascular diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for NAFLD and NASH are used, then existing therapeutic options are available, but potent and selective HSD17B13 inhibition is lacking

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidenzyme selectivity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by designing compounds with specific heteroaryl substituents (pyridine, pyrimidine, triazine rings) at defined positions on the phenol core structure. This localized structural modification at specific molecular regions provides selective interaction with HSD17B13 enzyme active site, achieving both potent inhibition and enzyme selectivity simultaneously

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying substituent types (different heteroaryl groups), substitution patterns (positions 4, 5, 6 on phenol ring), and molecular properties (logP, pKa, molecular weight) to optimize the balance between therapeutic efficacy and selectivity. The compounds exhibit IC50 values in the nanomolar range while maintaining selectivity for HSD17B13 over other 17β-HSD isoforms

Inventive Principle:

Principle #35Parameter changes

2Reliability

If HSD17B13 inhibition is achieved, then lipogenesis modulation occurs, but potential off-target effects may arise

Engineering Contradiction:

Improvemetabolic modulationVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies inversion by designing the inhibitor to bind in the reverse orientation or through alternative interactions compared to natural substrates. The heteroaryl substituted phenol compounds engage the enzyme active site through flipped binding modes, achieving potent inhibition while avoiding interactions with other enzymes that process natural substrates, thus reducing off-target effects

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent uses the heteroaryl substituent groups as intermediary elements that mediate between the phenol core and the enzyme active site. These intermediary heteroaryl rings (pyridine, pyrimidine, triazine) provide specific hydrogen bonding and pi-stacking interactions that ensure selective binding to HSD17B13 while preventing off-target interactions with other enzymes

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250340546A1HSD17b13 inhibitors

Publication Date: 2025.11.06 BOEHRINGER INGELHEIM INT GMBH

AI summary

The present invention encompasses heteroaryl substituted 2,6-difluorophenol compounds of formula (I), wherein the groups A1 to A3, and Z have the meanings given in the claims and specification, their use in pharmaceutical compositions which contain these compounds and their use as medicaments, especially to interfere with the progression of liver disease from steatosis to later stages of nonalcoholic steatohepatitis, fibrosis, and cirrhosis.