Cannabinoid receptor mediating iminopyrazole compounds
Inventors
Kunos, George • Iyer, Malliga • Cinar, Resat • Rice, Kenner C.
Assignees
US Department of Health and Human Services
Publication Number
US-10787419-B2
Publication Date
2020-09-29
Expiration Date
2033-11-12
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Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, comprising (i) a CB1 receptor mediating scaffold conjugated to (ii) a second therapeutic scaffold.
Core Innovation
The invention provides novel compounds that act as CB1 receptor mediators conjugated to secondary therapeutic scaffolds. These compounds are designed with specific chemical structures, including amidino- or hydrazino-containing groups, which enable selective peripheral activity. The core scaffold and substituents are carefully defined to optimize pharmacological properties while avoiding central nervous system penetration. Additionally, these compounds include structural features that allow dual activity, targeting secondary pathways such as iNOS and AMPK, thereby enhancing their therapeutic versatility.
One of the key objectives of the invention is to address limitations of previous CB1 antagonists, which caused neuropsychiatric side effects due to central activity. By emphasizing peripheral selectivity, the compounds aim to treat metabolic conditions like obesity, diabetes, and fatty liver disease effectively. Moreover, their dual activity on other targets supports anti-inflammatory and anti-fibrotic effects, broadening their application scope and improving safety profiles.
Claims Coverage
The patent includes multiple claims centered on chemical compounds with specific structures targeting CB1 receptors, characterized by various substituents and functional groups to confer activity and selectivity. Three core inventive features are identified within these claims.
Compound structures having a CB1 receptor mediating scaffold conjugated to therapeutic moieties
The claims delineate compounds featuring a CB1 receptor targeting scaffold linked to other therapeutic groups, including amidino, hydrazino, or thiol-based moieties. These structures are characterized by various substituents at multiple positions, such as alkyl, cycloalkyl, aryl, or heteroaryl groups, with defined ranges for substituent types and counts, enabling precise control over pharmacology.
Incorporation of biguanidino-containing moieties as part of the compound structure
Claims specify compounds with biguanidino groups, with definitions for R4, R6, R7, and R8 substituents, allowing hydrogen or alkyl substitutions. These features are integral for enhancing therapeutic efficacy, especially relating to metabolic regulation and receptor binding affinity.
Specific structural embodiments of compounds targeting CB1 receptors
Claims describe particular molecular structures with detailed substituents that define the chemical scaffold. These embodiments aim for high specificity and peripheral activity, with structural variations designed to optimize therapeutic effects while reducing central side effects.
The independent claims predominantly focus on chemically defined compounds with CB1 receptor mediating scaffolds linked to secondary therapeutic groups, including biguanidino or similar functionalities. These claims encompass detailed chemical substitutions and specific structural forms aimed at producing safe, effective CB1 modulators with dual therapeutic actions for metabolic and inflammatory conditions.
Stated Advantages
The compounds selectively target peripheral CB1 receptors, greatly reducing the risk of neuropsychiatric side effects associated with central CB1 antagonists.
They provide comprehensive treatment benefits for metabolic syndrome by decreasing food intake, promoting weight loss, reversing insulin and leptin resistance, and alleviating fatty liver and dyslipidemia.
The dual activity on secondary targets such as iNOS and AMPK enhances their anti-inflammatory, anti-fibrotic, and metabolic regulatory effects, broadening their therapeutic potential.
Good oral bioavailability, chemical stability, and a plasma half-life ranging from 1 to 16 hours make these compounds suitable for therapeutic use.
Low or absent activity on cytochrome P450 enzymes minimizes potential drug-drug interactions, increasing safety and usability.
Documented Applications
Treating obesity, diabetes (including types 1 and 2), fatty liver disease (NAFLD and ALD), and related metabolic disorders.
Managing co-morbidities of obesity such as cardiovascular diseases, hypertension, gout, neurodegenerative diseases, and certain cancers.
Treating fibrosis and liver cancers.
Preventing or reversing excess adipose tissue accumulation and improving metabolic homeostasis.
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