Deuterium-Enriched Pyrimidine Compounds for Pulmonary Arterial Hypertension
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Solution Overview
Problem
Current treatments for pulmonary arterial hypertension and related conditions are limited by their non-specificity and side effects, such as liver toxicity, and lack effective oral agents, necessitating the development of safer and more specific therapeutic options.
Innovation Solution
Development of deuterium-enriched pyrimidine compounds with 5-HT2B receptor antagonist activity, which can be used as pharmaceutical agents to treat pulmonary arterial hypertension, resistant hypertension, congestive heart failure, and other central nervous system disorders, offering improved pharmacokinetic and toxicological profiles compared to non-isotopically enriched compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-specific endothelin receptor antagonists are used to treat pulmonary arterial hypertension, then pulmonary arterial dilation is achieved, but liver toxicity occurs requiring monitoring
Solution Approach 1:
The patent applies local quality by introducing deuterium atoms at specific positions on the pyrimidine molecule (positions 2, 4, 6, or 8) to create localized modifications that improve metabolic stability and reduce liver toxicity while maintaining the overall therapeutic mechanism of endothelin receptor antagonism and 5-HT2B receptor antagonism
Solution Approach 2:
The patent changes the isotopic parameter of hydrogen atoms to deuterium, which alters the physical and chemical properties of the molecule including metabolic stability and pharmacokinetic profile, thereby reducing liver toxicity while maintaining therapeutic effectiveness
2Reliability
If systemically administered prostacyclin analogs are used for pulmonary arterial hypertension, then pulmonary arterial dilation is achieved, but the treatment requires intravenous or subcutaneous administration
Solution Approach 1:
The deuterium substitution changes the pharmacokinetic parameters of the compound, improving oral bioavailability and metabolic stability, which enables convenient oral administration while maintaining therapeutic effectiveness for pulmonary arterial hypertension
3Reliability
If 5-HT2B receptor antagonists are developed for selective targeting, then selectivity for diseased vasculature is improved, but the molecular structure becomes more complex
Solution Approach 1:
The patent achieves selective targeting of 5-HT2B receptors by introducing deuterium at specific local positions on the pyrimidine molecule, which provides the necessary molecular complexity for selectivity while keeping the overall structure relatively simple and tractable
Solution Approach 2:
The patent creates a composite molecular structure combining a pyrimidine core with deuterium substitution and specific substituents (R1-R20 groups) to achieve both 5-HT2B receptor antagonism and selective targeting of diseased vasculature
Data Source
AI summary
The present invention is concerned with deuterium-enriched pyrimidine compounds of formula I, their derivatives and pharmaceutically acceptable salts and methods of use thereoffor the treatment of pulmonary arterial hypertension, pulmonary hypertension associated with chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, hypertension, ischemic stroke, angina pectoris, congestive heart failure, arrhythmia, arterial fibrillation, Alzheimer's disease, cognition impairment, memory decline, and schizophrenia, and depression.