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-11485709-B2
Publication Date
2022-11-01
Expiration Date
2033-11-12
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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
Endocannabinoids act on cannabinoid receptors CB1 and CB2, mediating effects such as increased appetite, lipid biosynthesis and storage, insulin and leptin inhibition, and promotion of inflammation and fibrosis. Existing CB1 receptor blockers, like the prototype compound rimonabant, were effective against obesity and metabolic syndrome but caused neuropsychiatric side effects, leading to their withdrawal and halting further therapeutic development.
The invention discloses compounds comprising a CB1 receptor mediating scaffold conjugated to a second therapeutic scaffold, forming hybrid compounds. These compounds are designed to selectively target peripheral CB1 receptors, thereby minimizing CNS side effects. Dual activity compounds targeting CB1 and additional cellular targets like iNOS inhibition or AMPK activation aim to improve metabolic efficacy and address insulin resistance, fibrosis, and inflammation.
The compounds have defined chemical structures with amidino-, hydrazino- or thiol-containing moieties and various substituents. The compounds can be selective CB1 inverse agonists or neutral antagonists that preferentially act on peripheral tissues. They demonstrate improved chemical stability, low brain penetrance indicated by low brain/plasma concentration ratio, binding affinity in the 0.1-20 nM range to CB1, and high CB1/CB2 selectivity. Some compounds metabolize in vivo to release therapeutic second scaffolds such as metformin, enhancing efficacy by combined mechanisms.
Claims Coverage
The patent discloses three independent claims directed to methods of treating various diseases using compounds with specific structural features.
Method for treating fibrosis, cirrhosis, liver cancer, or reversing insulin resistance
Administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt/ester, having a defined chemical structure with features including X as SO2, a and c as one, and b as zero.
Method for treating metabolic and obesity-related diseases
Administering a therapeutically effective amount of a compound or salt/ester, having a specified chemical structure with substituent R14 optionally being amino. The diseases include fibrosis, cirrhosis, liver cancer, obesity, diabetes, fatty liver diseases, co-morbidities of obesity, dyslipidemias, diabetic nephropathy, and gout, or reversing insulin resistance.
Method for treating diseases using compounds with specific 'A' moieties and substituents
Administering therapeutically effective amounts of compounds with the 'A' moiety selected from amidino derivatives such as —NH—C(═NH)—CH3 or —NH—C(═NH)—NH—C(═O)—CH3 and substituents R′ like CF3 or C1, for treating fibrosis, cirrhosis, liver cancer, obesity, diabetes, fatty liver disease, co-morbidities, dyslipidemias, diabetic nephropathy, or gout, or reversing insulin resistance.
The claims cover methods of treating fibrosis, liver diseases, obesity, diabetes, and associated conditions by administering compounds with specific structural features that mediate CB1 receptor activity and, in some embodiments, include defined substituents that contribute to efficacy in these indications.
Stated Advantages
The compounds improve all aspects of metabolic syndrome including reducing food intake, body weight, reversing insulin and leptin resistance, reducing hepatic steatosis and improving dyslipidemia.
They provide therapeutic benefits for obesity, diabetes, fatty liver diseases, and fibrosis while minimizing central nervous system side effects due to low brain penetrance.
The dual activity compounds can inhibit iNOS and/or activate AMPK, providing enhanced efficacy over previous CB1 receptor blockers.
The compounds have improved chemical stability and low cytochrome P450 interaction resulting in fewer drug-to-drug interactions.
Documented Applications
Treatment of obesity, diabetes (including type 1 and type 2), non-alcoholic and alcoholic fatty liver disease, and metabolic syndrome co-morbidities such as arteriosclerotic heart disease and gout.
Treatment of fibrosis, liver cirrhosis, and liver cancer.
Prevention or reversal of adipose tissue deposition in subjects to mitigate obesity and related disorders.
Interested in licensing this patent?