PTPRD inhibitors and uses thereof
Inventors
Uhl, George Richard • Henderson, Ian M. • Wang, Wei • Prisinzano, Thomas
Assignees
University of Kentucky Research Foundation • US Department of Veterans Affairs • University of Arizona
Publication Number
US-11987564-B2
Publication Date
2024-05-21
Expiration Date
2042-05-02
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Abstract
Disclosed are small molecule PTPRD inhibitors and uses thereof. Methods of using the PTPRD inhibitors include methods of treating, preventing, or delaying the progression of a disorder responsive to PTPRD inhibition, including for example nicotine dependence, addiction, obesity, metabolic syndrome, and substance-use disorders such as stimulant-use disorders and opioid-use disorders.
Core Innovation
The invention relates to small molecule inhibitors of receptor-type tyrosine-protein phosphatase delta (PTPRD) and their use. The compounds act as potent inhibitors of PTPRD's phosphatase activity, which is associated with several addiction-related phenotypes. By inhibiting PTPRD's ability to dephosphorylate certain substrates, including addiction-associated substrates, the compounds are useful for treating, preventing, or delaying the progression of addiction or dependence to substances such as nicotine, opioids, and stimulants. They also have utility in treating obesity and metabolic syndrome.
PTPRD is a highly expressed, largely neuronal receptor-type protein tyrosine phosphatase involved in intracellular signaling. Human genetic and mouse model studies show variation in PTPRD signaling contributes to addiction-related phenotypes, including vulnerability to develop substance-use disorders, reward from stimulants and opioids, and ability to quit use of opioids or nicotine. Small molecule inhibitors of PTPRD can reduce reward from addictive substances and thus treat or prevent such disorders.
The problem solved concerns the lack of approved therapeutics that reduce the rewarding properties of addictive substances that contribute to addiction and dependence. Substance abuse and nicotine dependence cause major health and social problems, with no licensed anti-addiction therapeutics based on reducing drug reward. The disclosed compounds address this unmet medical need by serving as PTPRD inhibitors that reduce reward from addictive substances, thereby providing therapies for substance-use disorders, nicotine dependence, obesity, and metabolic syndrome.
Claims Coverage
The patent includes independent claims directed to compounds of Formula (I), methods of treating disorders responsive to PTPRD inhibition using those compounds, methods of inhibiting PTPRD activity, and the manufacture of medicaments with such compounds. The main inventive features describe the chemical structures and their use in treatment and inhibition of PTPRD.
Compounds of Formula (I) with specified substituents
A compound having a structure represented by Formula (I) with defined substituents R1, R2, and R3, where R1 is hydrogen or C1-C2 alkyl, and R2 is C1-C2 alkyl, with detailed chemical group definitions for each substituent and restriction on certain R3 groups when R1 is hydrogen and R2 is methyl.
Compounds of Formula (II) as substructure variants
Compounds represented by Formula (II) as specific structural variants of Formula (I) with particular substituents on R3 as defined in claim 3.
Methods of treating PTPRD-responsive disorders using the compounds
A method for treating a disorder responsive to inhibition of PTPRD by administering an effective amount of the compounds of Formula (I) or Formula (II), including disorders such as substance-use disorders, nicotine dependence, obesity, or metabolic syndrome, with specifications on substituents in some claims.
Methods for inhibiting PTPRD activity using the compounds
Inhibiting PTPRD activity by contacting PTPRD with an effective amount of compounds of Formula (I) or (II) having specified substituents to inhibit the enzyme’s phosphatase function.
Use in manufacture of medicaments for treating PTPRD-related disorders
Using compounds of Formula (I) or Formula (II) in the manufacture of a medicament for treatment, prevention, or delayed progression of nicotine dependence, substance-use disorders (including stimulant or opioid-use disorders), obesity, metabolic syndrome, or other PTPRD-responsive disorders.
The independent claims cover the novel compounds with defined structures, their medicinal and therapeutic methods of use in treating PTPRD-responsive disorders, methods of PTPRD inhibition, and their use in manufacture of medicaments, focusing on defined substituents and chemical properties relevant to activity and therapeutic use.
Stated Advantages
The compounds are potent inhibitors of PTPRD phosphatase activity, useful for treating and preventing addiction and dependence disorders.
They reduce the reward associated with addictive substances such as nicotine, opioids, and stimulants, addressing an unmet need in anti-addiction therapy.
They have utility in treating obesity and metabolic syndrome, expanding potential therapeutic applications beyond addiction.
The disclosed compounds have improved understanding of PTPRD/ligand interactions, facilitating development of better inhibitors.
Documented Applications
Treatment, prevention, or delaying progression of substance-use disorders including stimulant-use and opioid-use disorders.
Treatment, prevention, or delaying progression of nicotine dependence.
Treatment, prevention, or delaying progression of obesity.
Treatment, prevention, or delaying progression of metabolic syndrome.
Use in humans and mammals to reduce reward from addictive substances and prevent addiction associated health consequences.
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