Macrocyclic TYK2 Allosteric Inhibitor for Brain-Penetrant Selectivity
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Solution Overview
Problem
Current TYK2 inhibitors lack selectivity against JAK family members, leading to adverse events like cardiovascular incidents and venous thromboembolism, and there is a need for a highly selective TYK2 inhibitor with strong blood-brain barrier penetration for treating neurodegenerative diseases.
Innovation Solution
Development of a macrocyclic compound that acts as a highly selective TYK2 allosteric inhibitor with strong blood-brain barrier penetration, targeting the TYK2 JH2 pseudokinase domain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If TYK2 inhibitors target the JH1 kinase catalytic domain, then they can inhibit TYK2 activity, but they exhibit limited selectivity and cause adverse events such as cardiovascular incidents and venous thromboembolism
Solution Approach 1:
The patent extracts the inhibitory function from the JH1 catalytic domain and relocates it to the JH2 pseudokinase domain. By designing compounds that specifically bind to the JH2 domain of TYK2, the invention separates the desired inhibitory effect from the harmful cross-reactivity with other JAK family members that occurs when targeting JH1
Solution Approach 2:
The patent applies local quality by creating compounds with specific molecular structures that selectively interact with unique features of the TYK2 JH2 domain. The compounds contain specific structural motifs (such as heterocyclic rings and substitution patterns) that match the spatial and chemical characteristics of the TYK2 JH2 binding pocket, enabling high selectivity
2Reliability
If Deucravacitinib binds to the TYK2 JH2 pseudokinase domain, then it achieves high selectivity over other JAK family members, but it still exhibits certain activity against the JH2 domain of JAK1
Solution Approach 1:
The patent modifies molecular parameters such as ring size, substitution positions, and functional group types to fine-tune selectivity. By systematically varying these structural parameters, the invention optimizes the compound's fit to TYK2 JH2 while reducing affinity for JAK1 JH2, thereby eliminating JAK1-related adverse effects
3Adaptability or versatility
If TYK2 inhibitors are developed for treating autoimmune diseases, then they can reduce inflammation, but there are no highly selective TYK2 inhibitors reported with strong brain penetration for neurodegenerative diseases
Solution Approach 1:
The patent modifies physicochemical parameters including molecular weight, lipophilicity, and hydrogen bonding capacity to enhance blood-brain barrier penetration. These parameter changes enable the compounds to cross into the central nervous system while maintaining their selective TYK2 inhibitory activity, opening therapeutic potential for neurodegenerative diseases
Data Source
AI summary
The present disclosure relates to a macrocyclic compound, a pharmaceutical composition and use thereof. The compound has a structural formula as shown in Formula I. The macrocyclic compound is a highly selective TYK2 allosteric inhibitor with strong blood-brain barrier penetration that can be used to regulate TYK2-mediated diseases.