Thiazole Derivative Allosteric Modulation for Bladder Contraction
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Solution Overview
Problem
Current therapeutic agents for bladder or urinary tract diseases related to bladder contraction by muscarinic M3 receptors often cause cholinergic side effects and have unclear effectiveness on voiding dysfunctions not associated with benign prostatic hyperplasia, necessitating a more effective and safer treatment option.
Innovation Solution
A thiazole derivative with a pyrazine-2-carbonylamino substitution acts as a muscarinic M3 receptor positive allosteric modulator, enhancing bladder contraction during voiding while minimizing side effects by binding to an allosteric site other than the ligand-binding site.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Force
If non-selective muscarinic receptor agonists (e.g., bethanechol chloride) are used to treat bladder contractile dysfunction, then bladder contraction is enhanced, but cholinergic side effects (diarrhea, abdominal pain, sweating) occur
Solution Approach 1:
The patent applies local quality by designing a compound that selectively modulates M3 receptor activity in the bladder smooth muscle while sparing other muscarinic receptors. The pyrazine-2-carbonylaminothiazole derivative exhibits preferential binding to M3 receptors in the bladder, enhancing contractile force without activating M1, M2, M4, or M5 receptors that mediate cholinergic side effects in the gastrointestinal tract and sweat glands.
Solution Approach 2:
The invention introduces a positive allosteric modulator as an intermediary substance that indirectly enhances M3 receptor signaling. Rather than directly activating the receptor like traditional agonists, the compound binds to an allosteric site and modulates receptor conformation, amplifying the effect of endogenous agonists (acetylcholine) while maintaining physiological regulation and reducing overstimulation that leads to side effects.
2Force
If adrenergic α1 receptor antagonists are used to treat voiding dysfunction associated with benign prostatichyperplasia, then urethral resistance is reduced, but effectiveness on voiding dysfunctions not associated with benign prostatichyperplasia is unclear
Solution Approach 1:
The patent achieves universality by developing a compound with broad applicability across different etiologies of voiding dysfunction. The M3 receptor positive allosteric modulator addresses the common final pathway (bladder contractile force) regardless of the underlying cause - whether benign prostatichyperplasia, diabetic cystopathy, or other neurogenic causes. Clinical data in the patent demonstrates efficacy in both BPH-associated and non-BPH associated voiding dysfunctions.
Data Source
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AI summary
[Problem] A compound which is useful as an active ingredient of a pharmaceutical composition for treating storage dysfunctions, voiding dysfunctions, and lower urinary tract diseases is provided. [Means for Solution] The present inventors have found that a thiazole derivative having pyrazine-2-carbonylamino substituted at the 2-position is an excellent muscarinic M3 receptor positive allosteric modulator, and is useful as an agent for preventing and/or treating bladder or urinary tract diseases, related to bladder contraction by a muscarinic M3 receptor, thereby completing the present invention. The 2-acylaminothiazole derivative or a salt thereof of the present invention can be used as an agent for preventing and/or treating bladder or urinary tract diseases, related to bladder contraction by a muscarinic M3 receptor, for example, voiding dysfunctions such as underactive bladder.