Brain-Penetrant sGC Stimulators for NO-Independent CNS Treatment
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Solution Overview
Problem
Current therapies for treating central nervous system (CNS) diseases are inadequate due to the lack of effective compounds that can cross the blood-brain barrier and stimulate soluble guanylate cyclase (sGC) independently of nitric oxide (NO), leading to insufficient modulation of cGMP levels and downstream effector activities.
Innovation Solution
Development of sGC stimulators, such as those listed in Table 1, which can cross the blood-brain barrier and enhance cGMP levels by directly stimulating sGC, either alone or in combination with NO-independent mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used to treat CNS diseases, then treatment is provided, but the compounds cannot effectively cross the blood-brain barrier to stimulate sGC
Solution Approach 1:
The patent modifies the chemical structure of sGC stimulators to change their pharmacokinetic parameters, specifically their ability to cross the blood-brain barrier. The compounds are designed with specific molecular properties that enable them to penetrate the blood-brain barrier while maintaining sGC stimulatory activity, thus resolving the contradiction between effectiveness and barrier penetration.
2Reliability
If NO-dependent sGC activation is used, then sGC stimulation is achieved, but the therapy is insufficient for treating CNS diseases with inadequate cGMP modulation
Solution Approach 1:
The patent extracts the NO-dependency from the sGC activation mechanism by developing NO-independent sGC stimulators. These compounds directly activate sGC without requiring NO as a second messenger, thereby providing more reliable and potent cGMP modulation for treating CNS diseases with better therapeutic efficacy.
Solution Approach 2:
The patent introduces heme-containing compounds as intermediary agents that can activate sGC independently of NO. These heme-based stimulators serve as direct activators that bridge the gap between administration and sGC activation, providing reliable cGMP modulation without depending on NO availability in the CNS.
3Reliability
If existing sGC stimulators are used, then sGC activity is increased, but the compounds lack specificity and efficacy for CNS disease treatment
Solution Approach 1:
The patent develops sGC stimulators with local quality by designing compounds that specifically target sGC in the CNS while minimizing off-target effects. The heme-containing compounds are structurally optimized to provide selective activation of sGC in neural tissues, enhancing specificity for CNS disease treatment while maintaining reliable sGC activation.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
These sGC stimulators provide therapeutic benefits for a wide range of CNS diseases by increasing cGMP levels, modulating protein kinases and ion channels, and addressing various neurological disorders, including Alzheimer's, Parkinson's, and psychiatric conditions, with improved efficacy and specificity.
Implementation Method 1
sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts guanosine 5′-triphosphate (GTP) into the secondary messenger cyclic guanosine 3′,5′-monophosphate (cGMP).
Implementation Method 2
NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes
Data Source
AI summary
The present disclosure relates to the use of stimulators of soluble guanylate cyclase (sGC), pharmaceutically acceptable salts thereof and pharmaceutical formulations or dosage forms comprising them, alone or in combination with one or more additional agents, for the treatment of various CNS diseases, wherein an increase in sGC stimulation, or an increase in the concentration of nitric oxide (NO), or cyclic guanosine 3′5′-monophosphate (cGMP) or both, or an upregulation of the NO pathway is desirable.