Pyrazolo Piperidine Carboxylic Acids for sGC Activation
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Solution Overview
Problem
Current sGC activators for treating cardiovascular and cardiac diseases have limitations due to poor pharmacokinetic properties and side effects, such as short half-life and systemic toxicity, which affect their therapeutic efficacy and dosing frequency.
Innovation Solution
Development of substituted pyrazolo piperidine carboxylic acids and their salts, which act as potent, haem-independent sGC activators with improved pharmacokinetic profiles, including higher bioavailability and longer half-life, reducing the need for frequent dosing.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If current sGC activators are used for treating cardiovascular diseases, then therapeutic effect is achieved, but half-life is short and dosing frequency must be increased
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of sGC activators through substitution patterns on the pyrazolo piperidine core. Specific substituents (R1-R6 groups) are introduced to alter pharmacokinetic parameters, extending half-life from minutes to hours while maintaining therapeutic efficacy. This structural optimization allows transition from frequent dosing to once-daily or less frequent regimens.
2Reliability
If current sGC activators are used to achieve therapeutic effects, then cardiovascular benefits are obtained, but systemic toxicity occurs
Solution Approach 1:
The patent employs local quality principles by designing substituents that enhance tissue-specific distribution and retention of the sGC activator. The R1-R6 groups are selected to improve pharmacokinetic properties including plasma protein binding and tissue penetration, thereby concentrating therapeutic effect at the target site while reducing systemic exposure and toxicity.
Solution Approach 2:
The patent introduces pharmacokinetic intermediaries in the form of specific functional groups (e.g., carboxylic acid derivatives, heterocyclic substituents) that modulate the compound's interaction with plasma proteins and tissue barriers. These intermediary structures act as buffers, reducing peak plasma concentrations and extending elimination half-life, thus decoupling therapeutic effect from toxic exposure.
3Reliability
If current sGC activators are administered to improve cardiovascular outcomes, then therapeutic effect is achieved, but bioavailability is poor
Solution Approach 1:
The patent applies parameter changes by optimizing the lipophilicity and molecular weight of the sGC activator through strategic substitution. The R1-R6 groups are selected to balance membrane permeability and solubility, improving oral bioavailability from poor to moderate/good levels while maintaining the compound's ability to activate soluble guanylate cyclase effectively.
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 compounds demonstrate enhanced pharmacological activity and physicochemical properties, providing sustained therapeutic effects with improved bioavailability and reduced side effects, making them suitable for treating cardiovascular, cardiac, and other diseases like hypertension and pulmonary hypertension.
Implementation Method 1
These compounds are potent activators of soluble guanylate cyclase... The compounds according to the invention lead to vasorelaxation, inhibition of platelet aggregation and lowering of blood pressure and increase of coronary and renal blood flow. These effects are mediated via direct haem-independent activation of soluble guanylate cyclase and an increase of intracellular cGMP.
Data Source
AI summary
The invention relates to substituted pyrazolo piperidine carboxylic acids, their salts and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular and cardiac diseases, preferably heart failure with reduced and preserved ejection fraction (HFrEF, HFmrEF and HFpEF), hypertension (HTN), peripheral arterial diseases (PAD, PAOD), cardio-renal and kidney diseases, preferably chronic and diabetic kidney disease (CKD and DKD), cardiopulmonary and lung diseases, preferable pulmonary hypertension (PH), and other diseases, preferably neurodegenerative diseases and different forms of dementias, fibrotic diseases, systemic sclerosis (SSc), sickle cell disease (SCD), wound healing disorders such as diabetic foot ulcer (DFU).