Benzoic Acid Compounds for Uric Acid Reduction
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Solution Overview
Problem
Current medications for treating elevated uric acid levels, such as gout and hyperuricemia, often come with significant side effects and poor patient compliance due to these issues, and there is a need for safer and more effective agents particularly in organ transplant recipients and for conditions related to soluble uric acid levels.
Innovation Solution
A compound represented by Formula I, which inhibits the uric acid transporter URAT1, is administered to reduce uric acid concentration in the blood or increase its excretion, thereby treating or preventing conditions like gout, hyperuricemia, renal dysfunction, and cardiovascular diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current medications (allopurinol, probenecid, benzbromarone) are used to reduce uric acid levels, then uric acid production or excretion is improved, but significant side effects occur including liver failure, Stevens-Johnson syndrome, and poor patient compliance
Solution Approach 1:
The patent modifies the chemical structure of benzbromarone by replacing the bromine atom with different substituents (fluoro, chloro, methyl, methoxy, nitro groups) to change the pharmacological parameters of the compound. This structural modification aims to maintain or improve uric acid excretion efficacy while reducing the toxic side effects associated with the parent compound, particularly liver failure and other severe adverse reactions
Solution Approach 2:
The invention introduces specific local modifications at the 2-position of the benzoic acid ring system by adding various electron-withdrawing or electron-donating groups. These localized chemical changes alter the compound's interaction with URAT1 transporter and metabolic enzymes, thereby improving the therapeutic index by maintaining uric acid lowering activity while reducing hepatotoxicity and other harmful effects
2Reliability
If xanthine oxidase inhibitors (allopurinol) are used to reduce uric acid production, then uric acid levels are lowered, but severe dermatological reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis occur
Solution Approach 1:
The patent develops uricosuric agents that act as intermediary compounds to enhance uric acid excretion through the URAT1 transporter in the kidney, providing an alternative pathway that bypasses the xanthine oxidase enzyme system. This mediator approach allows uric acid reduction without triggering the immunological reactions and severe dermatological side effects associated with xanthine oxidase inhibitors like allopurinol
3Reliability
If uricosuric agents (probenecid, benzbromarone) are used to improve uric acid excretion, then renal clearance is enhanced, but liver failure and other severe side effects occur leading to market withdrawal in many countries
Solution Approach 1:
The patent creates a series of short-acting or rapidly metabolized uricosuric compounds with improved safety profiles. By designing molecules that are efficiently excreted and have shorter half-lives, the invention reduces cumulative hepatotoxicity while maintaining effective uric acid lowering during the active period, thereby avoiding the severe liver failure that led to the withdrawal of long-acting agents like benzbromarone
4Reliability
If current gout treatments are used to manage acute symptoms, then inflammation and pain are reduced, but patient compliance remains very poor due to side effects and lack of benefit
Solution Approach 1:
The patent addresses patient compliance by providing a comprehensive uric acid lowering regimen that can be segmented into different therapeutic options based on individual patient needs and tolerance. The series of compounds offers flexible dosing and mechanism-based selection, allowing clinicians to segment the treatment approach to maximize adherence while managing both acute and chronic aspects of gout
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 compound effectively lowers uric acid levels, reducing the severity and incidence of gout attacks and associated conditions, with a safer profile compared to existing treatments, and is particularly beneficial for organ transplant recipients and conditions linked to soluble uric acid.
Implementation Method 1
A compound represented by Formula I, which inhibits the uric acid transporter URAT1, is administered to reduce uric acid concentration in the blood or increase its excretion
Data Source
AI summary
Uric acid in mammalian subjects is reduced and excretion of uric acid is increased by administering a compound of Formula I. The uric acid-lowering effects of the compounds of this invention are used to treat or prevent a variety of conditions including gout, hyperuricemia, elevated levels of uric acid that do not meet the levels customarily justifying a diagnosis of hyperuricemia, renal dysfunction, kidney stones, cardiovascular disease, risk for developing cardiovascular disease, tumor-lysis syndrome, cognitive impairment, early-onset essential hypertension, and Plasmodium falciparum-induced inflammation.In Formula I, t is 0 or 1; q is 0 or 1; and r is 0, 1 or 2. R7 is hydrogen or alkyl having from 1 to 3 carbon atoms. R6 is hydrogen, hydroxy, halo, alkyl having from 1 to 3 carbon atoms, alkoxy having from 1 to 3 carbon atoms, nitro, thio, alkylthio, or cyano. X is C(O) or NH(R8) wherein R8 is hydrogen or alkyl having from 1 to 3 carbon atoms; provided that when X is C(O), r is 0 and t is 0. A is phenyl, unsubstituted or substituted by 1 or 2 groups selected from halo, hydroxy, methyl, ethyl, perfluoromethyl, methoxy, ethoxy, perfluoromethoxy, nitro, and amino; or a 5 or 6 membered heteroaromatic ring having 1 or 2 ring heteroatoms selected from N, S and O and the heteroaromatic ring is covalently bound to the remainder of the compound of Formula I by a ring carbon; or cycloalkyl having from 3 to 6 ring carbon atoms wherein the cycloalkyl is unsubstituted or one or two ring carbons are independently monosubstituted by methyl or ethyl.