Hemoglobin Modulator Compounds for Lower-Frequency Sickle Cell Dosing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for compounds that can treat disorders mediated by abnormal hemoglobin, such as HbS, with an improved pharmacokinetic profile relative to known modulators while maintaining or improving efficacy, allowing for favorable dosing regimens.
Innovation Solution
Development of compounds of formula I, their isotopically enriched analogs, stereoisomers, or prodrugs, and pharmaceutically acceptable salts, which increase oxygen affinity of hemoglobin and inhibit polymerization of HbS under hypoxic conditions, formulated into pharmaceutical compositions with excipients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known hemoglobin modulators are used to treat sickle cell disease, then efficacy in increasing oxygen affinity and inhibiting polymerization is achieved, but pharmacokinetic profile is suboptimal requiring higher and more frequent dosing
Solution Approach 1:
The patent modifies the chemical structure of known hemoglobin modulators by changing molecular parameters such as replacing hydrogen atoms with deuterium (isotopic substitution), modifying substituent groups (R1, R2, R3, R4), and altering core aromatic ring structures. These parameter changes improve pharmacokinetic properties including metabolic stability and half-life, thereby reducing dosing frequency while maintaining therapeutic efficacy in increasing oxygen affinity and inhibiting HbS polymerization
2Reliability
If hemoglobin modulators are administered to increase oxygen affinity, then polymerization inhibition is achieved, but pharmacokinetic limitations restrict dosing regimen optimization
Solution Approach 1:
The patent employs systematic parameter changes in the molecular structure of hemoglobin modulators, including variations in substituent groups (R1-R4), core ring structures (X, Y, Z), and isotopic composition. These modifications enhance metabolic stability and bioavailability, enabling more efficient dosing regimens that maintain effective polymerization inhibition while improving overall dosing efficiency and reducing treatment burden
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 effectively treat disorders mediated by hemoglobin, including sickle cell disease, by increasing oxygen affinity and preventing polymerization, offering improved pharmacokinetic profiles and potential for lower and less frequent dosing.
Implementation Method 1
Hemoglobin binds and releases oxygen through conformational changes
Implementation Method 2
HbS susceptible to polymerization under hypoxic conditions to give the HbS containing red blood cells their characteristic sickle shape
Data Source
AI summary
The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of hemoglobin, and methods for their use in treating disorders mediated by hemoglobin.