aPKC Inhibiting Compounds for Vascular Permeability Control
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Solution Overview
Problem
Current treatments for conditions characterized by abnormal vascular permeability, such as diabetic retinopathy and brain tumors, lack effective methods to inhibit or reduce vascular permeability, which is often mediated by atypical protein kinase C (aPKC) activation.
Innovation Solution
Development of compounds with specific structural formulas that inhibit or reduce vascular permeability by targeting and inhibiting aPKC activity, including administering compositions comprising these compounds to subjects to treat or prevent diseases associated with abnormal vascular permeability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for conditions characterized by abnormal vascular permeability, then existing therapeutic options are limited, but effective inhibition of vascular permeability is not achieved
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific molecular structures (formulas I-IV) that target aPKC enzymes. The compounds feature varied substituent groups (R1-R6, Ar) and structural parameters (n=0,1,2; X1=X2=O,S,NH or NMe/N) to optimize inhibitory activity against aPKC, thereby improving treatment effectiveness for vascular permeability disorders
Solution Approach 2:
The patent segments the broad class of PKC enzymes into specific atypical PKC isoforms (aPKC) as the therapeutic target. By focusing inhibition specifically on aPKC rather than all PKC isoforms, the patent provides a targeted therapeutic approach that improves reliability of treatment while addressing the specific pathophysiology of vascular permeability disorders
2Reliability
If vascular permeability is not inhibited, then disease progression continues, but effective inhibitory mechanisms are lacking
Solution Approach 1:
The patent converts the harmful effect of aPKC-mediated vascular permeability into a therapeutic opportunity by designing compounds that specifically inhibit aPKC activity. The compounds transform the pathological signaling pathway into a controlled therapeutic mechanism, reducing vascular permeability and preventing disease progression in conditions like diabetic retinopathy and macular edema
Solution Approach 2:
The patent introduces small molecule compounds as intermediary substances that mediate between the aPKC enzyme and its substrates. These compounds act as competitive inhibitors, binding to the aPKC active site and preventing phosphorylation of tight junction proteins, thereby controlling vascular permeability without directly affecting the underlying disease pathology
Data Source
AI summary
The invention provides a method of inhibiting atypical protein kinase C (aPKC) comprising contacting an aPKC with a compound having a structure selected from the group consisting of structural formulas (I) to (IX). The invention further provides a method of inhibiting or reducing vascular permeability. The method comprising administering to a subject a composition comprising an amount of a compound having a structure selected from the group consisting of structural formulas (I) to (IX) effective to inhibit or reduce vascular permeability. A method of treating or preventing a disease or disorder characterized by abnormal vascular permeability, a method of inhibiting angiogenesis, a method of inhibiting cancer cell proliferation, a formulation, and a method of preparing a formulation also are provided.