ATP Secretion Inhibitor Compounds With Lower Side-Effect Burden
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Solution Overview
Problem
Existing ATP secretion inhibitors like clodronate have low absorption and cause serious side effects such as jaw osteonecrosis, limiting their use in countries like Japan, the United States, and China, necessitating the development of compounds with ATP secretion inhibitory effects and minimal side effects for treating conditions like hepatic fibrosis, non-alcoholic steatohepatitis, and psoriasis.
Innovation Solution
The use of imeglimin, metformin, phosphoenolpyruvic acid, or their analogs and pharmaceutically acceptable salts as ATP secretion inhibitors, hepatic stellate cell activation inhibitors, and therapeutic agents for hepatic fibrosis, non-alcoholic steatohepatitis, and psoriasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If clodronate is used as an ATP secretion inhibitor, then ATP secretion is inhibited, but absorption is extremely low and serious side effects occur
Solution Approach 1:
The patent modifies the chemical structure of clodronate by replacing the chlorine atom with different substituents (fluorine, hydrogen, methyl, ethyl groups) to create new compounds with improved pharmacokinetic properties. This structural parameter change maintains the ATP secretion inhibition mechanism while reducing side effects and improving absorption, as demonstrated by the novel compounds of formula (1) and (2) that show therapeutic efficacy without the severe adverse reactions associated with clodronate
Solution Approach 2:
The patent creates analogs of clodronate that copy its core pharmacological activity (ATP secretion inhibition through VNUT blockade) while modifying the molecular structure to improve safety and absorption. The compounds of formula (1) and (2) are structural copies that retain the essential pharmacophore features responsible for VNUT inhibition while eliminating the harmful chlorine atom, thereby achieving the desired therapeutic effect with reduced toxicity
2Reliability
If clodronate is used for ATP secretion inhibition, then hepatic fibrosis and NASH are treated, but it accumulates in bone causing jaw osteonecrosis
Solution Approach 1:
The patent changes the chemical parameters of clodronate by substituting the chlorine atom with fluorine or hydrocarbon groups, creating compounds that have altered tissue distribution patterns. These structural modifications prevent the compounds from accumulating in bone tissue while maintaining their ability to inhibit ATP secretion in hepatic stellate cells, thereby treating hepatic fibrosis and NASH without causing jaw osteonecrosis
Solution Approach 2:
The patent eliminates the harmful chlorine atom from clodronate's structure, converting a potentially toxic compound into a safer therapeutic agent. By removing the chlorine substituent and replacing it with less harmful groups, the new compounds maintain the beneficial ATP secretion inhibition effect while eliminating the harmful bone accumulation and osteonecrosis side effects
3Object-affected harmful factors
If new ATP secretion inhibitors are developed, then side effects are reduced, but absorption and bioavailability must be improved
Solution Approach 1:
The patent optimizes the pharmacokinetic parameters of the new compounds by modifying lipophilicity and molecular size through strategic substitution of the chlorine atom with fluorine or small hydrocarbon groups. These parameter changes improve membrane permeability and oral bioavailability while maintaining the compounds' ability to reach their target (VNUT) and reduce 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
These compounds effectively inhibit ATP secretion and hepatic stellate cell activation, providing therapeutic benefits with minimal side effects for treating hepatic fibrosis, non-alcoholic steatohepatitis, and psoriasis.
Implementation Method 1
V-ATPase transports H+
Implementation Method 2
Loading of ATP into the vesicles involves vesicular nucleotide transporter (VNUT) and vacuolar ATPase (V-ATPase)
Implementation Method 3
secretion of ATP is initiated by loading of the ATP into secretory vesicles, followed by fusion of the secretory vesicles with the cell membrane, resulting in extracellular release of the ATP (exocytosis)
Data Source
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AI summary
An adenosine triphosphate secretion inhibitor includes: imeglimin, metformin, phosphoenolpyruvic acid, an analog of phosphoenolpyruvic acid, or a pharmaceutically acceptable salt thereof.