Substituted Dipiperidine CCR2 Antagonists for Inflammatory Disease
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Solution Overview
Problem
There is a need for small molecule CCR2 antagonists to prevent, treat, or ameliorate inflammatory syndromes, disorders, or diseases resulting from MCP-1 induced monocyte and lymphocyte migration to a site of inflammation, as current treatments like MCP-1 antagonists and TNF-α antagonists have limitations.
Innovation Solution
Development of substituted dipiperidine compounds that act as CCR2 antagonists, specifically compounds of Formula (I) and their derivatives, which can inhibit the interaction between MCP-1 and CCR2, thereby reducing inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If MCP-1 antagonists or TNF-α antagonists are used to treat inflammatory diseases, then inflammatory response is suppressed, but treatment complexity and potential side effects increase
Solution Approach 1:
The patent modifies the chemical structure of CCR2 antagonists by changing parameters such as introducing specific functional groups (carboxylic acid, ester, amide) at defined positions in the molecule, and adjusting physical properties like lipophilicity and molecular weight to optimize binding affinity and selectivity for CCR2 receptor, thereby achieving effective inflammation suppression with reduced treatment complexity
Solution Approach 2:
The patent creates small molecule antagonists that replicate the binding capability of larger protein-based antagonists (MCP-1 antagonists, TNF-α antagonists) but with simplified molecular structures, enabling similar therapeutic effects through chemically simpler compounds that can be more easily administered and have fewer side effects
2Object-affected harmful factors
If protein-based antagonists (MCP-1 antibodies, TNF-α antagonists) are used, then inflammatory pathways are blocked, but manufacturing complexity and cost increase
Solution Approach 1:
The patent develops small molecule compounds that are chemically simpler, easier to synthesize, and more cost-effective to manufacture compared to protein-based antagonists, while maintaining sufficient efficacy to block inflammatory pathways, thereby reducing manufacturing complexity and cost
Solution Approach 2:
The patent replaces complex protein-based biological systems with chemically synthesized small molecules that achieve similar functional outcomes through purely chemical mechanisms, eliminating the need for complex protein expression, purification, and formulation processes
3Object-affected harmful factors
If conventional CCR2 antagonists are used, then monocyte migration is inhibited, but selectivity and potency are insufficient
Solution Approach 1:
The patent introduces specific functional groups at specific locations within the molecular structure to enhance binding affinity at the CCR2 receptor's active site, while maintaining overall molecular simplicity, thereby achieving high selectivity and potency for blocking monocyte migration without affecting other biological processes
Data Source
AI summary
The present invention comprises compounds of Formula (I) wherein: X, R1, R2, R3, and R4 are as defined in the specification. The invention also comprises a method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is type II diabetes, obesity and asthma. The invention also comprises a method of inhibiting CCR2 activity in a mammal by administration of a therapeutically effective amount of at least one compound of Formula (I).