Cannabinoid receptor mediating compounds
Inventors
Kunos, George • Iyer, Malliga • Cinar, Resat • Rice, Kenner C.
Assignees
US Department of Health and Human Services
Publication Number
US-11939297-B2
Publication Date
2024-03-26
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 discloses novel peripherally restricted cannabinoid receptor mediating compounds that comprise a CB1 receptor mediating scaffold conjugated to a second therapeutic scaffold. These compounds or pharmaceutically acceptable salts or esters thereof have specific structures defined by various substituted moieties, including amidino-containing, hydrazino-containing, or optionally substituted thiol groups. The compounds are designed to selectively target CB1 cannabinoid receptors, particularly in peripheral tissues such as adipose tissue, liver, muscle, lung, kidney, macrophages, pancreatic beta cells, and the gastrointestinal tract, with minimal or no interaction with CB1 receptors in brain tissue.
The problem being addressed is the neuropsychiatric side effects caused by earlier CB1 receptor blocking drugs, such as rimonabant, which, though effective against metabolic syndrome, were withdrawn due to these side effects preventing their therapeutic use. The invention aims to develop CB1 receptor mediating compounds with low brain penetrance to avoid such adverse central nervous system effects while maintaining beneficial metabolic effects.
Furthermore, the invention addresses the limited metabolic efficacy of existing CB1 receptor blocking drugs by designing dual activity compounds that act on more than one target within cells involved in metabolic processes. For example, the compounds generate metabolites that inhibit inducible nitric oxide synthase (iNOS) or activate adenosine monophosphate kinase (AMPK), both of which contribute to improved insulin resistance and reduced fibrosis and inflammation. Thus, the invention solves both safety and efficacy problems associated with current CB1 receptor modulation therapies.
Claims Coverage
The patent contains two claims, with one independent claim defining the compound structure and the other covering pharmaceutical compositions including the compound. The main inventive features include the specific compound formula and compositions.
Compound of defined formula
A compound with a specific chemical formula comprising a CB1 receptor mediating scaffold conjugated to a second therapeutic scaffold characterized by an amidino-containing, hydrazino-containing, or optionally substituted thiol group 'A' and variable substituents R1, R2, R3, R10-R21, X, M, and others as stipulated, providing peripheral selectivity and dual therapeutic activity.
Pharmaceutical composition containing the compound
A pharmaceutical composition comprising a therapeutically effective amount of the disclosed compound of the defined formula and at least one pharmaceutically acceptable additive suitable for administering the compound to subjects.
The independent claims cover the novel cannabinoid receptor mediating compound characterized by a specific chemical structure and the pharmaceutical compositions that contain such compounds for therapeutic use, focusing on peripheral CB1 receptor modulation and dual activity through conjugation with a second therapeutic scaffold.
Stated Advantages
The compounds exhibit reduced neuropsychiatric side effects due to low brain penetrance, targeting peripheral CB1 receptors.
They improve metabolic syndrome aspects including reduced food intake, body weight, insulin and leptin resistance, hepatic steatosis, and dyslipidemia.
The compounds show dual activity by generating metabolites that inhibit iNOS or activate AMPK, enhancing therapeutic efficacy against fibrosis, diabetes, and obesity.
Improved chemical stability with a plasma half-life of 1-16 hours facilitates better pharmacokinetics.
Low or no cytochrome P450 activity reduces potential drug-drug interactions.
Documented Applications
Treatment of obesity, diabetes (including type 1 and 2), non-alcoholic and alcoholic fatty liver disease, and co-morbidities of obesity such as arteriosclerotic heart disease and gout.
Treatment of fibrosis and liver cancer in subjects.
Prevention or reversal of adipose tissue deposition to reduce incidence or severity of obesity and related co-morbidities.
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