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-9765031-B2
Publication Date
2017-09-19
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 relates to compounds comprising a CB1 receptor mediating scaffold conjugated to a second therapeutic scaffold, or pharmaceutically acceptable salts or esters thereof. The disclosed compounds have structures including amidino-containing, hydrazino-containing, or optionally substituted thiol moieties, and a variety of substituents as outlined in the specification. The invention encompasses cannabinoid receptor mediating compounds, in particular CB1 receptor selective compounds, which may be inverse agonists or neutral antagonists, with peripheral restriction to minimize central nervous system effects. These compounds may also possess secondary activities such as inducible nitric oxide synthase (iNOS) inhibition or AMP-activated protein kinase (AMPK) activation, either directly or via metabolites.
The problem being solved arises from the metabolic syndrome, obesity, diabetes, fibrosis, and related conditions which are mediated in part by CB1 receptor activation. Previously developed CB1 receptor blockers, such as rimonabant, showed therapeutic efficacy but caused neuropsychiatric side effects due to brain penetration, leading to their market withdrawal. There is a need for CB1 receptor blocking drugs with reduced brain penetrance to avoid these side effects while retaining metabolic efficacy. Additionally, the compounds aim to improve metabolic efficacy by incorporating dual therapeutic activities targeting related pathways such as iNOS or AMPK. The compounds disclosed address this by providing peripherally restricted CB1 receptor mediating agents that reduce food intake, body weight, insulin resistance, and fibrosis without neuropsychiatric adverse effects.
Claims Coverage
The patent includes one independent claim defining a compound with a specified chemical structure and its pharmaceutically acceptable salts or esters. This claim defines the core chemical features of the invention.
Compound having a specified CB1 receptor mediating structure
The compound has a defined chemical structure with an 'A' moiety selected from amidino-containing, hydrazino-containing, or optionally substituted thiol groups, with a plurality of possible substituents and configurations, including sulfur or selenium atoms, and variable substitution patterns specified by parameters a, b, c, m, x, y, d, and z.
Peripheral selectivity for CB1 receptors
The compound preferentially targets CB1 receptors in peripheral tissues, showing low or no interaction with CB1 receptors in brain tissue, characterized by brain to plasma maximum concentration ratios less than 0.1, preferably less than 0.05, or especially less than 0.025.
Pharmaceutical composition containing the compound
A pharmaceutical composition is claimed that comprises the compound and at least one pharmaceutically acceptable additive.
Method of treating metabolic and fibrotic diseases
Methods are claimed for treating obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, co-morbidities of obesity (including metabolic syndrome, dementia, heart disease, hypertension, etc.), dyslipidemias, diabetic nephropathy, and gout by administering a therapeutically effective amount of the compound while causing substantially no adverse neuropsychiatric effects.
The independent claims cover novel compounds with defined chemical structures acting as peripherally selective CB1 receptor mediators, their pharmaceutical compositions, and therapeutic methods for metabolic and fibrotic diseases. These compounds address the problem of neuropsychiatric side effects by reduced brain penetrance, possess dual activity including metabolic and anti-inflammatory actions, and provide benefits in treating obesity-related conditions.
Stated Advantages
Reduced neuropsychiatric side effects due to peripheral restriction and low brain penetrance.
Improved metabolic effectiveness including reduced food intake, body weight, insulin resistance, hepatic steatosis, and dyslipidemia.
Dual action addressing CB1 receptor activity and secondary pathways such as iNOS inhibition and AMPK activation to enhance therapeutic benefits.
Chemical stability leading to suitable plasma half-lives (1-16 hours, preferably 4-8 hours).
Low cytochrome P450 activity reducing potential for drug-drug interactions.
Documented Applications
Treatment of obesity, diabetes (including type 1 and type 2), non-alcoholic and alcoholic fatty liver disease.
Treatment of co-morbidities of obesity such as metabolic syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous stasis ulcers, pulmonary hypoventilation syndrome, sleep apnea, snoring, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
Treatment of fibrosis and liver cancer.
Prevention or reversal of adipose tissue deposition.
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