Deuterated Pentoxifylline for Renal Impairment Toxicity
Solution Overview
Problem
There is a continuing need for new compounds and compositions to treat diseases and conditions benefiting from pentoxifylline and related compounds while minimizing the risk of toxic reactions and adverse effects, particularly in patients with renal impairment.
Innovation Solution
The development of compositions comprising specific compounds, a second therapeutic agent, and a carrier for treating diseases and conditions, including the use of deuterated analogs of pentoxifylline and its metabolites, which aim to mitigate toxic reactions and improve therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pentoxifylline is administered to treat diseases and conditions, then therapeutic efficacy is improved, but risk of toxic reactions and adverse effects increases, particularly in patients with renal impairment
Solution Approach 1:
The patent applies parameter changes by substituting hydrogen atoms with deuterium atoms in the pentoxifylline molecule structure. This isotopic substitution modifies the metabolic parameters of the drug, specifically slowing down CYP450-mediated metabolism. The deuterated analogs exhibit altered pharmacokinetic parameters including extended half-life and reduced formation of toxic metabolites, thereby maintaining therapeutic efficacy while reducing toxicity, particularly in renal impairment patients
2Reliability
If pentoxifylline is administered to patients with renal impairment, then therapeutic benefit is provided, but accumulation of toxic metabolites occurs
Solution Approach 1:
The deuterated analogs of pentoxifylline modify the metabolic parameter of CYP450 enzyme activity through kinetic isotope effects. This parameter change reduces the rate of metabolite formation, particularly reducing the accumulation of toxic metabolites M-4 and M-5 that normally accumulate in renal impairment patients. The altered metabolic parameter maintains therapeutic benefit while preventing toxic metabolite accumulation
3Reliability
If deuterated analogs of pentoxifylline are used, then metabolism is modulated and tolerability is enhanced, but molecular structure complexity increases
Solution Approach 1:
The patent applies local quality by making selective isotopic substitutions at specific positions in the pentoxifylline molecule rather than uniform substitution throughout. The deuterium atoms are placed at specific locations (e.g., positions 1, 3, 7, or 8 of the purine ring system) to achieve the desired metabolic modulation with minimal structural complexity increase. This localized modification approach maintains tolerability and efficacy while limiting structural complexity
Data Source
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AI summary
A pharmaceutical composition comprising: a. an effective amount of a compound of Formula B: or a pharmaceutically acceptable salt thereof; b. a second therapeutic agent selected from insulin or insulin analogues, glucagon-like-peptide-1 (GLP-1) receptor agonists, sulfonylurea agents, biguanide agents, alpha-glucosidase inhibitors, PPAR agonists, meglitinide agents, dipeptidyl-peptidase (DPP) IV inhibitors, phosphodiesterase inhibitors, amylin agonists, CoEnzyme A inhibitors, and antiobesity agents; and c. a pharmaceutically acceptable car.