Heterocyclic P2Y14 receptor antagonists
Inventors
Jacobson, Kenneth A. • Yu, Jinha • Ciancetta, Antonella • Wen, Zhiwei • Jung, Young-Hwan
Assignees
US Department of Health and Human Services
Publication Number
US-11584736-B2
Publication Date
2023-02-21
Expiration Date
2039-02-11
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Abstract
Disclosed are compounds of formulas (I)-(IX) for treating or preventing a disease or disorder responsive to antagonism of a P2Y14R receptor agonist in a mammal in need thereof, wherein R1-R8, X, Y, Z, X′, Y′, Z′, and A are as defined herein, that are useful in treating an inflammatory such as asthma, cystic fibrosis, and sterile inflammation of the kidney.
Core Innovation
The invention provides compounds of formulas (I)-(IX) useful for antagonizing the P2Y14 receptor (P2Y14R) in mammals. These compounds include various substituents such as halo, trifluoromethyl, carboxylic acid derivatives, and heterocyclic groups described by the general formula. They are designed to treat or prevent diseases or disorders responsive to P2Y14R antagonism, particularly inflammatory conditions including asthma, cystic fibrosis, and sterile inflammation of the kidney.
The background identifies the problem of limited availability of selective competitive P2Y14R antagonists. Extracellular nucleotides activate P2 receptors to regulate immune responses, and the P2Y14R responds to endogenous agonists to mediate inflammatory activity by activating neutrophil motility. Because P2Y14R antagonists are potential therapeutic agents for inflammatory and other diseases, there is a clear need for more diverse competitive P2Y14R antagonists to expand treatment options.
Claims Coverage
The patent contains three independent claim groups covering compounds of formulas (I), (II), and (III)-(V), along with associated pharmaceutical compositions and methods of use. The main inventive features pertain to the specific chemical structures and their biological applications.
Compounds of formula (I) with specific heterocyclic substitutions
The compounds of formula (I) where X, Y, Z can be N or CH in specific arrangements; R1 is halo or trifluoromethyl; R2 includes COOH, CN, or CONH2; and A is selected from defined groups. These compounds are antagonists of the P2Y14 receptor. The claim also includes pharmaceutically acceptable salts of these compounds.
Compounds of formulas (III), (IV), or (V) with defined substituents
Compounds of formulas (III), (IV), or (V), wherein R7 is COOH or other specific groups; R8 includes alkyl or substituted amido groups; X, Y, Z, X', Y', and Z' have defined heteroatoms or carbon substituents; and salts thereof. These structures serve as P2Y14R antagonists and have specified substituent patterns.
Compound of formula (II) with tailored substituents and salts
Compounds of formula (II) where substituents R6, R7, R8 are finely defined among carboxyl groups, amides, and alkyl chains with variable length and functional groups. X, Y, Z, X', Y', and Z' likewise have specified values. This claim covers salts and pharmaceutical compositions having these compounds as active ingredients.
The claims together protect novel chemical entities with precise heterocyclic substitutions as P2Y14 receptor antagonists, compositions containing these compounds, and therapeutic methods for antagonizing P2Y14R and treating inflammatory diseases.
Stated Advantages
The compounds provide diverse competitive antagonists of the P2Y14 receptor, addressing the unmet need for such molecules.
They are useful in treating inflammatory conditions like asthma, cystic fibrosis, and sterile inflammation of the kidney.
The compounds show potency and selectivity as antagonists of P2Y14R as demonstrated in competitive binding assays.
Documented Applications
Treatment or prevention of inflammatory conditions in mammals, specifically asthma, cystic fibrosis, and sterile inflammation of the kidney.
Antagonism of the P2Y14 receptor in mammals, serving as a therapeutic mechanism.
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