Unsaturated Hydroxamic Acid Derivatives for Ammonia Reduction
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Solution Overview
Problem
Current treatments for ammonia-associated diseases such as hyperammonemia, particularly in conditions like hepatic encephalopathy and urea cycle disorders, are inadequate, as they often lead to cytotoxicity and mutagenicity, and fail to effectively reduce ammonia levels in the body.
Innovation Solution
Development of unsaturated hydroxamic acid derivatives with urease inhibitory activity, specifically 2-octynoHA, which are formulated for enteral or urinary administration to minimize systemic exposure and reduce side effects, utilizing a delivery system that converts into a less mutagenic form, thereby decreasing ammonia production and blood ammonia levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments for ammonia-associated diseases are used, then ammonia levels can be reduced, but cytotoxicity and mutagenicity occur
Solution Approach 1:
The patent modifies the chemical structure of hydroxamic acid derivatives by introducing unsaturated bonds (double or triple bonds) at specific positions in the molecule. This structural parameter change results in compounds that maintain urease inhibitory activity (ammonia level reduction) while reducing cytotoxicity and mutagenicity compared to conventional saturated hydroxamic acid derivatives
Solution Approach 2:
The patent creates composite molecular structures by combining hydroxamic acid core with unsaturated side chains (containing double or triple bonds). This composite approach allows the molecule to simultaneously achieve urease inhibition and reduced toxicity, resolving the contradiction between effectiveness and safety
2Productivity
If conventional treatments are used, then ammonia production is inhibited, but systemic exposure leads to increased side effects
Solution Approach 1:
The patent designs the hydroxamic acid derivative to have specific local properties including unsaturated bonds that confer urease inhibitory activity in the gut, while the overall molecular structure is optimized to minimize systemic absorption. This local quality approach ensures ammonia production inhibition at the site of action without widespread systemic effects
Solution Approach 2:
The patent employs a delivery system that facilitates rapid metabolism and elimination of the compound after it performs its urease inhibitory function in the gut. This short half-life approach ensures the compound acts where needed without persisting in the system long enough to cause significant side effects
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 unsaturated hydroxamic acid derivatives effectively inhibit urease activity, reducing ammonia production and blood ammonia levels without significant cytotoxicity or mutagenicity, offering a safer and more effective treatment for ammonia-associated diseases.
Implementation Method 1
These compounds have urease inhibitory activity
Data Source
AI summary
The present disclosure provides an enteral or urinary pharmaceutical formulation comprising (A) a compound of formula I, (I), wherein R1 is a C1-C3 alkyl; X is —C(R2)(R3)—C(R4)(R5)— or —C≡C—, wherein R2, R3, R4, and R5 are each independently H or In methyl; Y is —CH═CH—CH2—, —CH2—CH═CH—; —C≡C—CH2; —CH2—C≡C—; or —C(R7)(R8)—C(R9)(R10)—C(R11)(R12)—, wherein R7, R8, R9, R10, R11 and R12, are each independently H or methyl; provided that (1) when X is —C≡C—, Y is —C(R7)(R8)—C(R9)(R10)—C(R11)(R12)— and that (2) when Y is not —C(R7)(R8)—C(R9)(R10)—C(R11)(R12)—, X is —C(R2)(R3)—C(R4)(R5)—; and R6 is H or CH3, or a stereoisomer or a mixture thereof, or a pharmaceutically acceptable salt, ester or solvate thereof; and (B) (a) at least one pharmaceutically acceptable excipient; or (b) at least one other therapeutic agent; or (c) a combination of (a) and (b); and a use thereof for the treatment or prevention of an ammonia-associated disease or disorder, or a symptom thereof.