sGC Stimulator and Activator Combination for Oxidized Enzyme Treatment
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Solution Overview
Problem
Current sGC modulators are limited in their therapeutic scope due to dichotomous mechanisms of action, where sGC stimulators are ineffective on apo-sGC and require high doses for specific conditions, while sGC activators are needed for oxidative damage, lacking synergy and increasing the risk of dose-dependent side effects.
Innovation Solution
sGC stimulators are found to be equally effective on both heme-containing and apo-sGC, allowing for their use alone or in combination with sGC activators at lower doses, expanding therapeutic applications and reducing side effects by revising the taxonomy of sGC modulation drugs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If sGC stimulators are used to treat conditions with reduced NO levels, then cGMP production is enhanced through allosteric regulation, but the treatment is ineffective when sGC heme is oxidized or lost
Solution Approach 1:
The patent discovers that sGC stimulators can function on both heme-containing sGC and apo-sGC, making them universally applicable to different sGC states. This multi-functionality resolves the contradiction by allowing a single drug class to treat both NO deficiency conditions and oxidative damage conditions, eliminating the need for separate treatments for each condition.
Solution Approach 2:
The patent changes the understanding of the operational parameters of sGC stimulators by demonstrating they can activate apo-sGC in addition to heme-containing sGC. This parameter change expands the range of conditions treatable by sGC stimulators, resolving the contradiction between reliability for specific conditions and adaptability to different sGC states.
2Reliability
If sGC activators are used to treat oxidative damage conditions, then apo-sGC is activated, but high doses are required and synergistic effects with sGC stimulators are not utilized
Solution Approach 1:
The patent merges the use of sGC stimulators and sGC activators into a combined therapeutic approach. By combining these two drug classes, the patent achieves synergistic effects that enhance cGMP production while reducing the required doses of sGC activators, thus resolving the contradiction between reliability for oxidative damage treatment and the quantity of substance required.
Solution Approach 2:
The patent introduces sGC stimulators as intermediary agents that work in conjunction with sGC activators. The sGC stimulators enhance the effect of sGC activators on apo-sGC, creating a synergistic relationship that reduces the dose of sGC activators needed while maintaining or enhancing therapeutic effectiveness.
3Reliability
If high doses of sGC modulators are administered to ensure therapeutic effect, then cGMP deficiency is treated, but dose-dependent side effects increase
Solution Approach 1:
The patent combines sGC stimulators and sGC activators to achieve synergistic therapeutic effects at lower doses. This combination approach maintains reliable treatment of cGMP deficiency while reducing the doses required, thereby minimizing dose-dependent side effects and resolving the contradiction between therapeutic effectiveness and harmful side effects.
Solution Approach 2:
The patent changes the dosing parameters by using lower doses of combined sGC modulators compared to using high doses of single agents. This parameter change in dosing strategy maintains therapeutic effectiveness while reducing side effects, resolving the contradiction between reliability of therapeutic effect and object-affected harmful factors.
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
This approach enables broader treatment options for sGC dysfunction-related conditions, including cardiovascular diseases, with lower doses and reduced side effects, through synergistic action of sGC stimulators and activators, enhancing cGMP production and improving patient stratification.
Implementation Method 1
sGC stimulator compounds (abbreviated to 'sGCs' for an sGC stimulator, an sGC stimulator compound, which both have the same meaning here and throughout the text) that allosterically enhance sGC's apparent affinity for NO or its efficacy to stimulate cGMP formation
Implementation Method 2
By binding to sGC's histidine-ligated Fe(II)-heme, NO induces cleavage of the proximal histidine-Fe(II) bond and a subsequent conformational change in sGC that activates the enzyme's catalytic site, increasing its GTP to cGMP conversion rate by up to two orders of magnitude
Implementation Method 3
Oxidation or loss of sGC's heme, e.g. under disease conditions, yields so-called apo-sGC, which is no longer responsive to NO and represents a disruption of NO-cGMP signalling
Data Source
AI summary
The invention relates to a pharmaceutical composition comprising one or more stimulators of soluble guanylate cyclase (sGC), or a combination of at least one stimulator of sGC and at least one activator of sGC, for use in a method of treatment of a disease and/or a disorder that is/are associated with a deficiency of cyclic 3′,5′-guanosine monophosphate in the patient to be treated. The invention also relates to a therapeutic combination comprising a first unit dose comprising an sGC stimulator and a second unit dose comprising an sGC activator. The invention also relates to a therapeutic combination comprising a first unit dose comprising a first sGC stimulator and a second unit dose comprising a second sGC stimulator, for use in a method for the treatment of a disease and/or a disorder that is/are associated with a deficiency of cyclic 3′,5′-guanosine monophosphate in the patient to be treated. Furthermore, the invention relates to a kit comprising a pharmaceutical composition comprising one or more stimulators of sGC; a pharmaceutical composition comprising one or more stimulators of sGC and one or more activators of sGC; a therapeutic combination comprising a first unit dose comprising a first sGC stimulator and a second unit dose comprising a second sGC stimulator; or to a therapeutic combination comprising a first unit dose comprising an sGC stimulator and a second unit dose comprising an sGC activator.