Cyclic Derivatives Modulating CCR2 Receptor Activity
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Solution Overview
Problem
Current chemokine modulators lack sufficient efficacy and safety, particularly in terms of CCR2 receptor binding ability and ion channel selectivity, and have limitations in oral bioavailability and pharmacological characteristics for treating inflammatory, allergic, autoimmune, metabolic, cancer, and cardiovascular diseases.
Innovation Solution
Development of novel cyclic derivatives with improved pharmacological characteristics, including high oral bioavailability, potent CCR2 binding ability, and excellent ion channel selectivity, which are administered as pharmaceutical compositions to treat conditions such as diabetes, multiple sclerosis, and atherosclerosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing chemokine modulators are used, then some level of CCR2 binding is achieved, but ion channel selectivity and safety are insufficient
Solution Approach 1:
The patent modifies the chemical structure of existing chemokine modulators by changing molecular parameters such as introducing cyclic derivatives, modifying side chains, and adjusting functional groups. These structural parameter changes result in improved ion channel selectivity and enhanced safety profile while maintaining CCR2 binding activity, directly resolving the contradiction between binding efficacy and safety.
Solution Approach 2:
The invention creates composite molecular structures by combining different pharmacological moieties - integrating CCR2-binding fragments with ion channel-selective groups and safety-enhancing structural elements. This composite approach allows simultaneous optimization of binding ability, ion channel selectivity, and safety characteristics that cannot be achieved with single-fragment molecules.
2Reliability
If chemokine modulators are developed with high CCR2 binding ability, then treatment efficacy is improved, but oral bioavailability is limited
Solution Approach 1:
The patent optimizes molecular parameters including lipophilicity, molecular weight, and structural flexibility to enhance oral bioavailability. Specific modifications such as introducing bioavailable linkers, optimizing hydrogen bonding patterns, and adjusting steric parameters enable the compounds to cross biological membranes effectively while maintaining high CCR2 binding affinity.
Solution Approach 2:
The invention employs prodrug strategies and bioavailability-enhancing intermediaries that facilitate oral absorption and metabolism. These intermediary structures act as carriers that improve pharmacokinetic properties and enable effective delivery of the active CCR2-binding moiety through the gastrointestinal tract and blood-brain barrier.
3Reliability
If novel cyclic derivatives are synthesized with improved pharmacological characteristics, then treatment efficacy and safety are enhanced, but manufacturing complexity increases
Solution Approach 1:
The patent divides the synthesis of complex cyclic derivatives into modular segments using building block approaches. The molecules are constructed from pre-synthesized fragments that can be assembled through standardized coupling reactions, reducing overall synthesis complexity. This segmentation allows parallel production of multiple compounds and simplifies quality control.
Solution Approach 2:
The invention develops universal synthesis protocols and common intermediates that can be applied across multiple compound series. By creating multi-functional synthetic platforms and reusing common building blocks, the patent reduces redundant synthesis steps and simplifies manufacturing processes while maintaining the ability to generate diverse pharmacologically active compounds.
Data Source
AI summary
This invention relates generally to modulators of chemokine receptor activity having unexpected combination of desirable pharmacological properties. Pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases, particularly diabetes, Crohn's disease, atherosclerosis, and multiple sclerosis, along with methods of preparing compounds and intermediates therefor. Metabolites of active compounds are also provided herein, pharmaceutical compositions and use thereof are also provided.