Macrocyclic Compounds for Blood-Brain Barrier Crossing and Dual Inhibition
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Solution Overview
Problem
Current treatments for diseases involving cell death due to various causes and inflammation, particularly those affecting the central and peripheral nervous systems, lack effective compounds that can cross the blood-brain barrier and inhibit mitochondrial permeability transition while also blocking the pro-inflammatory activity of cyclophilin A.
Innovation Solution
Development of macrocyclic compounds that inhibit cyclophilin D to prevent mitochondrial permeability transition and block the cyclosporin A binding site of cyclophilin A, thereby preventing cell death and inflammation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments are used for diseases involving cell death and inflammation, then treatment options are available, but effective compounds that can cross the blood-brain barrier and inhibit mitochondrial permeability transition while blocking pro-inflammatory activity are lacking
Solution Approach 1:
The macrocyclic compound is designed to perform multiple functions simultaneously: crossing the blood-brain barrier, inhibiting mitochondrial permeability transition, and blocking the pro-inflammatory activity of cyclophilin A. This multi-functional approach resolves the contradiction by providing a single treatment that addresses multiple mechanisms of disease pathology, thereby improving reliability while achieving the versatility needed to cross the blood-brain barrier and target multiple pathways.
2Object-affected harmful factors
If compounds are developed to inhibit mitochondrial permeability transition, then cell death can be prevented, but pro-inflammatory activity of cyclophilin A may remain unblocked
Solution Approach 1:
The invention merges two separate protective functions into a single compound: inhibition of mitochondrial permeability transition (preventing cell death) and blocking of cyclophilin A's pro-inflammatory activity. By combining these two mechanisms in one macrocyclic compound, the patent simultaneously addresses both cell death and inflammation, resolving the contradiction between preventing harmful cell death factors and blocking harmful inflammatory factors.
3Reliability
If selective inhibition of cyclophilin D is achieved, then mitochondrial permeability transition is blocked, but crossing the blood-brain barrier may be compromised
Solution Approach 1:
The macrocyclic compound's molecular structure is optimized to change key parameters that enable both blood-brain barrier penetration and selective cyclophilin D inhibition. The compound's physicochemical properties (such as molecular size, lipophilicity, and structural features) are carefully tuned to allow efficient crossing of the blood-brain barrier while maintaining high affinity for cyclophilin D, thus resolving the contradiction between achieving reliable inhibition and ease of operation for barrier penetration.
Data Source
AI summary
The invention relates to selected macrocyclic compounds, and their use in the treatment or prevention of diseases and disorders. In particular, though not exclusively, the invention relates to the use of selected macrocyclic compounds in the treatment or prevention of diseases that are caused by (1) cell death due to various causes and (2) inflammation. Such diseases can affect all parts of the body, including the central and peripheral nervous systems, all organs and tissues, the muscles, the vasculature and the bones.