Triazole derivatives as P2Y14 receptor antagonists
Inventors
Jacobson, Kenneth A. • Junker, Anna • Uliassi, Elisa • Kiselev, Evgeny
Assignees
US Department of Health and Human Services
Publication Number
US-10683277-B2
Publication Date
2020-06-16
Expiration Date
2036-09-23
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Abstract
Described are compounds, which are antagonists of the P2Y14 receptor, for example, a compound of formula (I) in which ring A, R1, R2, R3, and n are as described herein. Also provided are dendron conjugates comprising the compounds, and methods of using the compounds, including a method of treating a disorder, such as inflammation, diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, a condition associated with metabolic syndrome, and asthma, and a method of antagonizing P214 receptor activity in a cell.
Core Innovation
The invention provides compounds of formula (I) and (II), which are antagonists of the P2Y14 receptor (P2Y14R), a G protein-coupled receptor involved in modulating functions in models of inflammation, diabetes, asthma, and other diseases. These compounds include variations of aryl, heteroaryl, and cycloalkyl groups and are designed to inhibit P2Y14R activity. Additionally, the invention includes dendron conjugates comprising these compounds and methods of using the compounds to treat disorders responsive to P2Y14R modulation.
The problem being solved arises from a limited set of known P2Y14R antagonists, which include chemotypes based on naphthoic acid and pyrido[4,3-d]pyrimidine derivatives. These known antagonists display potent activity but suffer from low oral bioavailability, low solubility, and difficulty of purification due to their high molecular weight and lipophilicity. There remains an unmet need for novel P2Y14R antagonists with improved potency, selectivity, and bioavailability for effective treatment of associated disorders.
The present invention addresses this need by providing compounds of formula (I) or (II) that reduce molecular weight and avoid the high lipophilicity seen in prior compounds, improving solubility and ease of purification. The compounds effectively antagonize P2Y14R activity and are desirable for therapeutic applications, including treatment of inflammation, diabetes, insulin resistance, hyperglycemia, lipid disorders, obesity, metabolic syndrome, and asthma. The invention also includes the preparation of dendron conjugates of these compounds for potential enhanced properties and methods of antagonizing P2Y14R in cells.
Claims Coverage
The patent includes multiple independent claims related to compounds of formulae (I), (II), (III), and (IV), pharmaceutical compositions, and methods of antagonizing P2Y14 receptor activity and treating diseases.
Compounds of formula (I) and (II) as P2Y14 receptor antagonists
Claims novel compounds defined by specific chemical formulas (I) and (II), wherein ring A or A', R1 or R1', R2 or R2', and R3 or R3' groups are selected from defined aryl, heteroaryl, cycloalkyl and other substituents, including pharmaceutically acceptable salts.
Dendron conjugates comprising compounds of formula (I) or (II)
Claims conjugates where compounds of formula (I) or (II) are linked via the nitrogen atom on the piperidinyl group to dendrons, optionally further linked to particles such as quantum dots or metallic particles via reactive sulfur-containing moieties.
Pharmaceutical compositions comprising the compounds or conjugates
Claims compositions comprising at least one compound of formula (I) or (II), or their dendron conjugates or salts, together with pharmaceutically acceptable carriers.
Methods of antagonizing P2Y14 receptor activity
Claims methods of antagonizing P2Y14 receptor activity in cells by administering the compounds of formula (I) or (II) or their conjugates or salts.
Methods of treating diseases using the compounds or conjugates
Claims methods of treating disorders such as inflammation, diabetes, and insulin resistance by administering effective amounts of the compounds of formula (I) or (II) or their conjugates or salts to subjects in need thereof.
The claims comprehensively cover novel triazole derivatives as P2Y14 receptor antagonists including specific chemical structures, their dendron conjugates, pharmaceutical compositions containing these compounds, and their use in methods of antagonizing the receptor and treating related diseases such as inflammation and diabetes.
Stated Advantages
The compounds reduce molecular weight and avoid high lipophilicity compared to prior art, improving solubility and purification.
Improved potency and selectivity as P2Y14 receptor antagonists.
Potential for improved oral bioavailability over previously known antagonists.
Structural integrity and feasibility of functionalization when conjugated to dendrons.
Documented Applications
Treatment of inflammation, diabetes (including type 2 diabetes), insulin resistance, hyperglycemia, lipid disorders, obesity, metabolic syndrome conditions, and asthma in mammals.
Antagonizing P2Y14 receptor activity in cells expressing the receptor from various tissues and organs.
Use of dendron conjugates linked to particles such as quantum dots or gold particles for therapeutic or research applications.
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