Substituted Cycloalkanes for NDI Urine Concentration
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Solution Overview
Problem
There is a need for therapeutic treatments that specifically target nephrogenic diabetes insipidus (NDI) to improve urine concentration in patients, as current treatments like metformin have side effects and there are no therapies addressing kidney function in NDI.
Innovation Solution
Administering a therapeutically effective amount of compounds of Formula I, such as NDI-5033, derivatives, or their pharmaceutically acceptable salts, optionally combined with cGMP-specific phosphodiesterase inhibitors, metformin, diuretics, or P2Y purinergic receptor antagonists, to enhance kidney response to vasopressin and improve urine concentration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If metformin is used to improve urine concentration in NDI patients, then urine concentration is improved, but lactic acidosis may occur as a side effect
Solution Approach 1:
The patent replaces the problematic long-term treatment (metformin) with a new compound (NDI-5033) that achieves the same therapeutic effect without the harmful side effects. The new compound acts as a short-term solution that does not accumulate harmful effects like lactic acidosis.
Solution Approach 2:
The patent extracts the beneficial effect of metformin (improved urine concentration) while removing the harmful side effect (lactic acidosis) by developing a new compound that selectively targets the desired physiological pathway without triggering the adverse metabolic response.
2Reliability
If hydrochlorothiazide and amiloride are used to manage dehydration in NDI, then dehydration is managed, but no specific therapy addresses kidney function in NDI
Solution Approach 1:
The patent applies local quality by designing a compound (NDI-5033) that specifically targets kidney function and vasopressin signaling pathways. Unlike general diuretics that affect multiple systems, this compound is tailored to act locally on renal tubules and vasopressin receptors to improve urine concentration without affecting other bodily functions.
Solution Approach 2:
The patent introduces an intermediary compound (NDI-5033) that mediates between the existing symptoms of NDI and the desired physiological outcome. This compound acts as a bridge by enhancing vasopressin signaling and urea transport specifically in the kidney, thereby addressing the root cause rather than just managing symptoms.
3Reliability
If vasopressin signaling is enhanced to improve urine concentration, then urine concentration improves, but existing compounds cause side effects like hypoglycemia or gastrointestinal distress
Solution Approach 1:
The patent uses a newly designed compound (NDI-5033) that provides the necessary vasopressin signaling enhancement without the metabolic side effects of older compounds. The compound is structurally optimized to avoid hypoglycemia and gastrointestinal issues while maintaining therapeutic efficacy.
Solution Approach 2:
The patent changes the chemical parameters of the therapeutic agent by developing NDI-5033 with modified molecular structure and properties. This structural modification alters the compound's interaction with biological systems, enhancing vasopressin signaling while eliminating adverse effects on glucose metabolism and gastrointestinal function.
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
Compounds of Formula I increase urine osmolality and reduce excessive urination and thirst in NDI models, effectively managing NDI symptoms without causing hypoglycemia or gastrointestinal distress.
Implementation Method 1
Vasopressin acts by increasing the phosphorylation and apical plasma membrane accumulation of the UT-Al urea transporter protein. Vasopressin has also been shown to regulate water transport via increasing phosphorylation and apical plasma membrane accumulation of the aquaporin-2 (AQP2) water channel.
Implementation Method 2
Vasopressin regulates urea transport through the activation of two cyclic AMP (cAMP) dependent signaling pathways: protein kinase A (PKA) and exchange protein activated by cAMP (Epac).
Data Source
AI summary
In certain embodiments, this disclosure relates to methods of treating or preventing nephrogenic diabetes insipidus comprising administering an effective amount of compounds of the class of alkyl carboxylic acids, such as 1,1′-(decane-1,10-diyl)bis(cyclopropane-1-carboxylic acid), pharmaceutical salts or derivatives thereof, and the class of alkyl amides, such as 1,1′-(dodecane-1,12-diyl)bis(cyclopropane-1-carboxamide), pharmaceutical salts or derivatives thereof, as described herein, to a subject in need thereof. In certain embodiments, the subject has been diagnosed with nephrogenic diabetes insipidus.