Urolithin Ester Prodrugs for Water Solubility
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Solution Overview
Problem
Urolithins, known for their therapeutic potential, are highly water-insoluble, making it challenging to formulate them into aqueous formulations for effective administration.
Innovation Solution
Development of compounds with ester groups that are hydrolyzed in the body to release urolithins, enhancing their water solubility and bioavailability, allowing for their absorption and delivery to the bloodstream.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If urolithins are used directly for therapeutic purposes, then they exhibit potent biological activity, but their high water insolubility makes formulation and administration difficult
Solution Approach 1:
The patent uses ester prodrugs as intermediary compounds that bridge the gap between water-insoluble urolithins and the need for aqueous formulation. The ester groups act as mediators that enhance water solubility during formulation and administration, then are hydrolyzed in the body to release the active urolithin compound, thus solving the contradiction between biological activity and ease of administration
Solution Approach 2:
The patent modifies the chemical parameters of urolithins by introducing ester groups at specific positions (such as C3-OH, C6-OH, or C8-OH positions). This parameter change transforms the physical-chemical properties of the molecule, specifically improving water solubility while maintaining the core structure necessary for biological activity. The esterified compounds can be formulated in aqueous solutions and are subsequently converted back to active urolithins in vivo
2Ease of operation
If ester prodrugs are developed to improve water solubility, then formulation and administration become easier, but the compounds require hydrolysis to release active urolithins
Solution Approach 1:
The patent segments the urolithin molecule by separating the core polyhydroxydibenzo[b,d]pyran-6-one structure from the hydroxyl groups, which are replaced by ester groups. This segmentation allows the core structure to maintain biological activity while the ester segments provide improved solubility and formulation properties. The segmented ester groups are then cleaved off through hydrolysis to release the active parent compound
Solution Approach 2:
The ester groups serve as temporary intermediary structures that facilitate formulation and administration. These intermediaries are designed to be stable enough for storage and handling but labile enough to be hydrolyzed in the body, thus mediating between the needs for solubility and the requirement for active compound delivery
3Quantity of substance
If urolithins are administered orally, then they can reach the bloodstream, but their water insolubility limits absorption and bioavailability
Solution Approach 1:
The patent changes the physical-chemical parameters of urolithins by introducing ester groups that increase water solubility. This parameter change directly addresses the absorption barrier, allowing the compounds to dissolve in gastrointestinal fluids and be absorbed into the bloodstream. The esterified compounds can be administered orally in aqueous or semi-aqueous formulations, and the ester groups are subsequently hydrolyzed to release the active urolithin in the circulation
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 compounds are more water-soluble than underivatized urolithins, enabling effective oral administration and bioavailability, providing a stable and efficient delivery of urolithins to treat various metabolic and mitochondrial-related disorders.
Implementation Method 1
Development of compounds with ester groups that are hydrolyzed in the body to release urolithins
Data Source
AI summary
The invention provides compounds of formula (I) or salts thereof:wherein:A, B, C, D, W, X, Y and Z are as defined in the specification, and at least one of A, B, C, D, W, X, Y and Z is OR1; each R1 being independently H or C(═O)R2, and at least one R1 group being C(═O)R2; where each R2 is selected from:CHR3NHR4, where R4 is H and R3 is a group selected from CH3, CH2CH(CH3)2, CH(CH3)CH2CH3, CH2Ph, CH2-3-(1H-indole), CH2CH2SCH3, CH2OH, CHOHCH3, CH2SH, CH2SeH and CH2PhpOH,wherein said R3 group can optionally be substituted by one or more groups selected from halogen, cyano, nitro, ORA or C1-C4 alkyl;or R3 and R4 together with the C and N atoms to which they are attached form a 5-membered heteroalkyl ring, wherein said heteroalkyl ring can optionally be substituted by one or more groups selected from halogen, cyano, nitro, ORA or C1-C3 alkyl,wherein RA is C1-C4 alkyl optionally substituted with one or more halogen, cyano or nitro groups.The compounds are effective pro-drugs for urolithins and they enable the ready delivery of urolithins to the site in the digestive tract where they can be absorbed into the body.