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-10683270-B2
Publication Date
2020-06-16
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 compounds, or pharmaceutically acceptable salts or esters thereof, comprising a CB1 receptor mediating scaffold conjugated to a second therapeutic scaffold. These compounds have structures characterized by specific chemical moieties including amidino-containing, hydrazino-containing, or optionally-substituted thiol groups, along with various other substituents on specified sites. The compounds aim to be peripherally restricted cannabinoid receptor mediating agents, selective for the CB1 receptor, and include inverse agonists or neutral antagonists that preferentially target CB1 receptors in peripheral tissues but not in the brain, thereby minimizing neuropsychiatric side effects.
The background problem addressed is that activation of CB1 receptors contributes to obesity and metabolic syndrome by increasing appetite, promoting lipid storage, and inducing inflammation and fibrosis. While CB1 receptor blocking drugs like rimonabant showed efficacy, their use was limited due to neuropsychiatric side effects caused by brain penetration. There is a need for CB1 receptor blockers that retain metabolic benefits without these central nervous system side effects. Additionally, limited metabolic efficacy could be improved by designing dual activity compounds that act on both CB1 receptors and other targets such as iNOS or AMPK, which influence insulin resistance and fibrosis.
The invention thus provides a new class of peripherally restricted CB1 receptor mediating compounds that have low brain penetration, improved chemical stability, suitable plasma half-life, and low cytochrome P450 activity to reduce drug interactions. These compounds may release therapeutically active secondary scaffolds, such as metformin, upon metabolic cleavage and thereby exhibit dual mechanisms of action. Their selective peripheral targeting and dual activity address the limitations of previous CB1 receptor antagonists by reducing metabolic syndrome features, obesity, diabetes, fibrosis, and liver cancer, while avoiding neuropsychiatric side effects.
Claims Coverage
The patent includes two independent claims directed to compounds with distinct chemical structures, as well as claims related to pharmaceutical compositions containing these compounds.
Compounds with defined cannabinoid receptor mediating scaffolds and substituents
A compound, or pharmaceutically acceptable salt or ester thereof, characterized by a specific chemical structure comprising moieties such as amidino-containing or hydrazino-containing groups, with multiple optional substituents on alkyl, cycloalkyl, aryl, heteroaryl, and related groups, and variable positions a, b, c, and others enabling structural diversity and selective CB1 receptor mediation.
Pharmaceutical compositions comprising the compounds
Compositions comprising a therapeutically effective amount of the compounds described, together with at least one pharmaceutically acceptable additive such as carriers, thickeners, diluents, buffers, preservatives, or surface active agents, enabling suitable administration and delivery.
The claims cover compounds with carefully defined chemical scaffolds that mediate cannabinoid receptor activity, particularly targeting CB1 receptors with peripheral restriction, and pharmaceutical compositions containing these compounds for therapeutic applications.
Stated Advantages
The compounds exhibit low brain penetrance, reducing neuropsychiatric side effects associated with CB1 antagonists.
They improve all aspects of the metabolic syndrome, including reducing food intake, body weight, insulin and leptin resistance, hepatic steatosis, and dyslipidemia.
They show dual activity by inhibiting iNOS and activating AMPK, enhancing anti-inflammatory, anti-fibrotic, and anti-diabetic effects.
The compounds possess improved chemical stability and pharmacokinetic properties with suitable plasma half-life and low cytochrome P450 interaction, minimizing drug-drug interactions.
They demonstrate higher efficacy in vivo than the prototype CB1 antagonist rimonabant, particularly in reducing liver fibrosis and improving metabolic parameters.
Documented Applications
Treatment of obesity, diabetes (including type 1 and type 2), and metabolic syndrome.
Treatment and prevention of non-alcoholic and alcoholic fatty liver disease and related liver fibrosis and liver cancer.
Treatment of co-morbidities associated with obesity such as arteriosclerotic heart disease, gout, hypertension, cardiovascular and metabolic disorders, and others.
Use to prevent or reverse deposition of adipose tissue to reduce severity or incidence of obesity and related conditions.
Pharmaceutical compositions for administration to subjects by various routes including oral, parenteral, transdermal, pulmonary, and others.
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