Quinoline-4-carboxylic Acid Analogs for Sustained DHODH Inhibition
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Solution Overview
Problem
Current DHODH inhibitors face challenges due to poor bioavailability and limited pharmaceutical efficacy, primarily attributed to issues with aqueous solubility and gastrointestinal uptake, which restricts their therapeutic effectiveness in treating proliferative disorders and cancers.
Innovation Solution
Development of 6-substituted-2-(phenylheteroaryl)quinoline-4-carboxylic acid analogs that act as DHODH inhibitors, demonstrating improved pharmacokinetic properties such as flip-flop kinetics and sustained pharmacokinetic profiles, enhancing their therapeutic potential for conditions like hematological cancers and graft-versus-host diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If currently described DHODH inhibitors are used, then DHODH inhibition activity is achieved, but bioavailability is poor due to poor aqueous solubility and GI uptake
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of DHODH inhibitors to alter their physical and chemical properties. Specifically, the compounds are designed with modified pharmacokinetic parameters including absorption rate constants, elimination rate constants, and distribution characteristics to achieve sustained release profiles and improved aqueous solubility while maintaining DHODH inhibition activity
Solution Approach 2:
The patent employs composite material principles by creating molecules with combined structural features that integrate both high DHODH binding affinity and improved pharmacokinetic properties. The disclosed compounds represent composite molecular structures that combine pharmacophoric elements for enzyme inhibition with structural modifications for enhanced solubility and absorption characteristics
2Reliability
If DHODH inhibitors are administered to treat proliferative disorders, then cell proliferation is inhibited, but pharmaceutical efficacy is limited due to bioavailability issues
Solution Approach 1:
The patent modifies pharmacokinetic parameters to enhance pharmaceutical efficacy. The disclosed compounds exhibit altered absorption and elimination rate constants that result in sustained plasma concentration profiles, ensuring adequate drug levels are maintained at the target site to maximize anti-proliferative effectiveness while minimizing dosing frequency
3Speed
If compounds with immediate release profile are used, then rapid DHODH inhibition is achieved, but sustained therapeutic effect is not maintained
Solution Approach 1:
The patent implements periodic action through sustained release pharmacokinetic profiles where the drug is released and maintained at therapeutic levels over extended periods. The modified compounds exhibit elimination rate constants that prevent rapid clearance, creating a sustained periodic presence in the system that maintains therapeutic effect without requiring frequent dosing
Solution Approach 2:
The patent achieves continuity of useful action by designing compounds with pharmacokinetic properties that maintain continuous therapeutic concentrations. The sustained release profiles ensure uninterrupted DHODH inhibition activity, keeping the drug effectively present in the biological system throughout the dosing interval to continuously suppress cell proliferation
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
The disclosed compounds exhibit enhanced bioavailability and sustained pharmacokinetic profiles, effectively inhibiting DHODH, thereby improving treatment outcomes for various disorders associated with cell proliferation and cancer, including acute myeloid leukemia and graft-versus-host diseases.
Implementation Method 1
DHODH uses cytochrome C in the electron transport chain as an electron acceptor for the oxidation of dihydroorotate to orotate
Data Source
AI summary
Disclosed herein are compounds, 6-substituted-2-(phenylheteroaryl)quinoline-4-carboxylic acid analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH). The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present disclosure.