Cannabinoid receptor mediating compounds
Inventors
Cinar, Resat • Kunos, George • Iyer, Malliga R. • Gahl, William A. • Gochuico, Bernadette R. • Malicdan, May Christine Vergara
Assignees
US Department of Health and Human Services
Publication Number
US-11155521-B2
Publication Date
2021-10-26
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 and (ii) a second therapeutic scaffold.
Core Innovation
The invention discloses compounds, or pharmaceutically acceptable salts or esters thereof, comprising a CB1 receptor mediating scaffold coupled with a second therapeutic scaffold. These compounds are designed to selectively target CB1 receptors in peripheral tissues while minimizing interaction with CB1 receptors in brain tissue, thereby retaining therapeutic efficacy with reduced neuropsychiatric side effects. The compounds include those with amidino-containing, hydrazino-containing, or optionally-substituted thiol moieties, and are characterized by specific substituents and structural configurations to optimize receptor binding and peripheral selectivity.
The problem being addressed arises from the limitations of existing CB1 receptor blocking drugs, such as rimonabant, which, despite being effective in treating metabolic syndrome, caused neuropsychiatric side effects limiting their clinical use. There is also an urgent need for therapies for fibrosis, particularly pulmonary fibrosis associated with Hermansky-Pudlak Syndrome (HPS), for which no FDA-approved treatments are currently available. The invention aims to develop CB1 receptor mediating compounds that overcome these challenges by minimizing brain penetrance and incorporating secondary therapeutic activities, such as inducible nitric oxide synthase (iNOS) inhibition or AMP-activated protein kinase (AMPK) activation, to enhance treatment efficacy in conditions including obesity, diabetes, fatty liver disease, fibrosis, and liver cancer.
Claims Coverage
The claims include one independent claim related to a method for treating alveolar inflammation in Hermansky-Pudlak Syndrome using specified compounds.
Method for treating alveolar inflammation with specific CB1 mediating compounds
Administering a therapeutically effective amount of compounds or their tautomers or pharmaceutically acceptable salts or esters, having specific formula structures that include CB1 receptor mediating scaffolds linked to amidino-containing or hydrazino-containing moieties for treating alveolar inflammation induced by Hermansky-Pudlak Syndrome (HPS).
Use of compounds with amidino-containing moieties
Utilizing compounds where the 'A' moiety is an amidino-containing group with defined substituents such as R4, R40, and R41 as hydrogen and R5 as C1-C6 alkyl, amino, or optionally-substituted thiol, optimizing therapeutic activity and selectivity.
Compounds characterized by SO2 as a linker (X) group
Employing compounds wherein the X group is SO2, contributing to the structural and functional properties of the therapeutic agents.
Oral administration of CB1 receptor mediating compounds
Providing the therapeutic compounds orally, enhancing patient compliance and practical administration for treating HPS-related alveolar inflammation.
Targeting subjects genetically predisposed to pulmonary fibrosis
Treating subjects with HPS-1, HPS-2, or HPS-4 gene mutations that predispose them to pulmonary fibrosis, indicating the therapeutic relevance of the compounds to genetically susceptible populations.
The claims focus on the therapeutic method for treating alveolar inflammation in Hermansky-Pudlak Syndrome using specifically structured CB1 receptor mediating compounds with defined amidino-containing moieties, SO2 linkers, oral administration, and applications to genetically susceptible individuals, capturing inventive features in compound composition and method of use.
Stated Advantages
The compounds provide high CB1 receptor affinity and selectivity with limited brain penetration to minimize neuropsychiatric side effects.
They offer dual-targeting capability by combining CB1 receptor blockade with either iNOS inhibition or AMPK activation, enhancing therapeutic efficacy.
They possess improved chemical stability resulting in suitable plasma half-life, reducing drug-to-drug interactions.
The compounds effectively reduce food intake, body weight, insulin and leptin resistance, hepatic steatosis, and improve metabolic parameters in animal models.
They demonstrate anti-fibrotic activity superior to existing CB1 antagonists in liver and pulmonary fibrosis models.
The compounds are orally bioavailable and suitable for practical therapeutic administration.
Documented Applications
Treatment of obesity, diabetes (including Type 2), and metabolic syndrome-related co-morbidities such as arteriosclerotic heart disease and gout.
Treatment and prevention of non-alcoholic and alcoholic fatty liver disease (NAFLD/AFLD), and associated liver cancer.
Treatment of pulmonary fibrosis, specifically pulmonary fibrosis related to Hermansky-Pudlak Syndrome (HPSPF) and idiopathic pulmonary fibrosis (IPF).
Use in reversing or preventing adipose tissue deposition and obesity.
Treatment of fibrosis in multiple organs including liver and lung.
Treatment of alveolar inflammation induced by Hermansky-Pudlak Syndrome.
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