5-Hydroxyl-1,7-Naphthyridine Compounds for Endogenous EPO Production
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Solution Overview
Problem
Current treatments for anemia related to chronic diseases, such as rheumatoid arthritis and inflammatory bowel disease, face challenges due to the high cost and limited bioavailability of exogenous erythropoietin (EPO), which requires frequent injections and can induce immunogenicity, limiting patient convenience and effectiveness.
Innovation Solution
Development of 5-hydroxyl-1,7-naphthyridine compounds substituted with aryloxy or heteroaryloxy groups that inhibit HIF prolyl hydroxylase, thereby stabilizing hypoxia-inducible factor α (HIF-α) and promoting the production of endogenous EPO, offering a potential alternative to exogenous EPO therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous EPO is used to treat anemia, then the effectiveness of anemia treatment is improved, but the treatment cost increases and patient convenience deteriorates
Solution Approach 1:
The patent enables the body's own cells to produce EPO by inhibiting PHD enzymes, which normally degrade HIF-α. By administering small molecule compounds that block PHD activity, the endogenous erythroid cells are stimulated to synthesize EPO autonomously, eliminating the need for external EPO injections and improving patient convenience while maintaining treatment effectiveness
Solution Approach 2:
The patent introduces small molecule compounds as intermediaries that mediate between the administered drug and the EPO production system. These compounds selectively inhibit PHD enzymes, thereby indirectly stimulating EPO production through the HIF-α pathway, rather than administering EPO directly. This intermediary approach allows for easier administration and reduced immunogenicity
2Reliability
If exogenous EPO is used to treat anemia, then the effectiveness of anemia treatment is improved, but the treatment cost increases
Solution Approach 1:
The patent employs small molecule compounds as inexpensive alternatives to expensive macromolecular EPO proteins. These small molecules can be synthesized more cheaply and administered orally or via other convenient routes, reducing the overall treatment cost while achieving the same therapeutic effect of increasing EPO levels and treating anemia
3Reliability
If exogenous EPO is used to treat anemia, then the effectiveness of anemia treatment is improved, but immunogenicity increases
Solution Approach 1:
The patent uses small molecule compounds as intermediaries that indirectly stimulate EPO production through enzymatic inhibition, rather than administering exogenous EPO protein directly. This indirect approach avoids the immunogenicity associated with foreign proteins, as the small molecules are less likely to trigger immune responses while still achieving the desired increase in endogenous EPO levels
Solution Approach 2:
By stimulating the body's own cells to produce EPO through PHD inhibition, the patent ensures that the EPO is endogenous and thus immunologically compatible. This self-service approach eliminates the immunogenicity problem inherent in exogenous EPO administration, as the produced EPO is recognized as self by the immune system
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
The 5-hydroxyl-1,7-naphthyridine compounds effectively inhibit HIF prolyl hydroxylase, enhancing the production of EPO and improving anemia treatment outcomes for chronic disease-related conditions by stabilizing HIF-α, potentially reducing treatment costs and improving patient convenience.
Implementation Method 1
The 5-hydroxyl-1,7-naphthyridine compounds effectively inhibit HIF prolyl hydroxylase
Implementation Method 2
prolyl at positions 402, 564 in the ODDD region of HIF-a was oxidized by prolyl hydroxylase to form 4-hydroxyprolyl
Implementation Method 3
HIF-a can form a stable dimer with HIF-b. After this dimer enters the nucleus, it activates the expression of important enzymes or enzyme systems such as glucose metabolism-related enzymes, GLUT-1, erythropoietin and vascular endothelial growth factor (VEGF)
Implementation Method 4
PHD transfers an oxygen atom to the 4-position of the prolyl molecule to form a hydroxyprolyl, and meanwhile converts 2-OG into one carbon dioxide molecule and succinic acid
Implementation Method 5
converts 2-OG into one carbon dioxide molecule and succinic acid
Data Source
AI summary
The present invention relates to a compound of 5-hydroxyl-1,7-naphthyridine substituted by aryloxy or heteroaryloxy, a preparation method thereof and a pharmaceutical use thereof. In particular, the compound has the following Formula (I), wherein R2 and R3 are each independently H; R1 is H or C1-C3 alkyl; Ar is an aromatic ring or a heteroaromatic ring selected from a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring and a substituted benzene ring. The present invention also relates to the method for preparing the compound, pharmaceutical compositions comprising the compound or pharmaceutically acceptable salts thereof, and uses of the compound or pharmaceutically acceptable salts thereof in the preparation of a medicine for inhibiting HIF prolyl hydroxylase or a medicine for promoting the generation of endogenous EPO.