n-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide and Body-Weight

Selective type 1 cannabinoid (CB1) receptor antagonists may assist with smoking cessation by restoring the balance of the endocannabinoid system, which can be disrupted by prolonged use of nicotine. They also seeks to address many smokers' reluctance to persist with a quit attempt because of concerns about weight gain.. To determine whether selective CB1 receptor antagonists (currently rimonabant and taranabant) increase the numbers of people stopping smoking To assess their effects on weight change in successful quitters and in those who try to quit but fail.. We searched the Cochrane Tobacco Addiction Review Group specialized register for trials, using the terms ('rimonabant' or 'taranabant') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, CINAHL and PsycINFO, using major MESH terms. We acquired electronic or paper copies of posters of preliminary trial results presented at the American Thoracic Society Meeting in 2005, and at the Society for Research on Nicotine and Tobacco European Meeting 2006. We also attempted to contact the authors of ongoing studies of rimonabant, and Sanofi Aventis (manufacturers of rimonabant). The most recent search was in January 2011.. Types of studies Randomized controlled trialsTypes of participants Adult smokersTypes of interventions Selective CB1 receptor antagonists, such as rimonabant and taranabant. Types of outcome measures The primary outcome is smoking status at a minimum of six months after the start of treatment. We preferred sustained cessation rates to point prevalence, and biochemically verified cessation to self-reported quitting. We regarded smokers who drop out or are lost to follow up as continuing smokers. We have noted any adverse effects of treatment.A secondary outcome is weight change associated with the cessation attempt.. Two authors checked the abstracts for relevance, and attempted to acquire full trial reports. One author extracted the data, and a second author checked them.. We found three trials which met our inclusion criteria, covering 1567 smokers (cessation: STRATUS-EU and STRATUS-US), and 1661 quitters (relapse prevention: STRATUS-WW). At one year, the pooled risk ratio (RR) for quitting with rimonabant 20 mg was 1.50 (95% confidence interval (CI) 1.10 to 2.05). No significant benefit was demonstrated for rimonabant at 5 mg dosage. Adverse events included nausea and upper respiratory tract infections. In the relapse prevention trial, smokers who had quit on the 20 mg regimen were more likely to remain abstinent on either active regimen than on placebo; the RR for the 20 mg maintenance group was 1.29 (95% CI 1.06 to 1.57), and for the 5 mg maintenance group 1.30 (95% CI 1.06 to 1.59). There appeared to be no significant benefit of maintenance treatment for the 5 mg quitters. One trial of taranabant was not included in our meta-analyses, as it followed participants only until end of treatment; at eight weeks it found no benefit for treatment over placebo, with an OR of 1.2 (90% CI 0.6 to 2.5). For rimonabant, weight gain was reported to be significantly lower among the 20 mg quitters than in the 5 mg or placebo quitters. During treatment, overweight or obese smokers tended to lose weight, while normal weight smokers did not. For taranabant, weight gain was significantly lower for 2-8 mg versus placebo at the end of eight weeks of treatment. In 2008, post-marketing surveillance led the European Medicines Agency (EMEA) to require Sanofi Aventis to withdraw rimonabant, because of links to mental disorders. The development of taranabant was also suspended by Merck & Co because of unacceptable adverse events.. From the trial reports available, rimonabant 20 mg may increase the chances of quitting approximately 1½-fold. The evidence for rimonabant in maintaining abstinence is inconclusive. Rimonabant 20 mg may moderate weight gain in the long term. Taranabant 2-8 mg may moderate weight gain, at least in the short term. In 2008, development of both rimonabant and taranabant was discontinued by the manufacturers.

Topics: Amides; Body Weight; Humans; Piperidines; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Receptor, Cannabinoid, CB1; Rimonabant; Secondary Prevention; Smoking; Smoking Cessation; Smoking Prevention

To evaluate the efficacy, safety and tolerability of taranabant in obese and overweight patients.. Double-blind, randomized, placebo-controlled study.. Patients were >or=18 years old, with body mass index of 27-43 kg m(-2), and 51% with metabolic syndrome (MS) randomized to placebo (N=417) or taranabant 2 mg (N=414), 4 mg (N=415) or 6 mg (N=1256) for 104 weeks.. Key efficacy measurements included body weight, waist circumference (WC), lipid and glycemic end points.. On the basis of risk/benefit assessments, the 6-mg dose was discontinued during year 1 (patients on 6 mg were down-dosed to 2 mg or placebo) and the 4-mg dose was discontinued during year 2 (patients on 4 mg were down-dosed to 2 mg). Changes from baseline in body weight at week 52 (all-patients-treated population, last observation carried forward analysis) were -2.6, -6.6 and -8.1 kg, respectively, for placebo and taranabant 2 and 4 mg (both doses P<0.001 vs placebo). For patients who completed year 1, changes from baseline in body weight at week 104 were -1.4, -6.4 and -7.6 kg for placebo and taranabant 2 and 4 mg, respectively (both doses P<0.001 vs placebo). The proportions of patients at weeks 52 and 104 who lost at least 5 and 10% of their baseline body weight were significantly higher and the proportions of patients who met criteria for MS were significantly lower for taranabant 2 and 4 mg vs placebo. The incidence of adverse experiences classified in the gastrointestinal, nervous, psychiatric, cutaneous and vascular organ systems were generally observed to be dose related with taranabant vs placebo.. Taranabant at the 2- and 4-mg dose was effective in achieving clinically significant weight loss over 2 years and was associated with dose-related increases in adverse experiences. On the basis of these and other data, an assessment was made that the overall safety and efficacy profile of taranabant did not support its further development for the treatment of obesity.

Topics: Adult; Aged; Aged, 80 and over; Amides; Anti-Obesity Agents; Body Mass Index; Body Weight; Diet, Reducing; Double-Blind Method; Female; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Pyridines; Receptor, Cannabinoid, CB1; Risk Assessment; Treatment Outcome; Young Adult

It has been proposed that cannabinoid-1 receptor inverse agonists might be effective for smoking cessation. We evaluated this hypothesis with the cannabinoid-1 receptor inverse agonist taranabant.. Adults who smoked > or =10 cigarettes a day for >1 year and had an expired CO level of > or =10 ppm participated in a randomized, double-blind, 8-week, study of taranabant (N = 159) or placebo (N = 158). Taranabant was titrated from 2 mg once daily to 8 mg once daily. Patients received smoking cessation counseling. The primary efficacy endpoint was continuous abstinence, defined as no cigarettes assessed by daily patient self-report and verified by breath CO level (<10 ppm) and plasma cotinine test (<10 ng/ml), during the last 4 weeks of the 8-week treatment period.. The percentage of patients achieving continuous abstinence was 7.5% for taranabant 2-8 mg and 6.3% for placebo (odds ratio = 1.2 [90% confidence interval (CI), 0.6, 2.5], P = 0.678). Change from baseline in body weight in the taranabant 2-8-mg group was -1.5 (90% CI, -1.8, -1.3) versus 0.6 kg (90% CI, 0.4, 0.9) in the placebo group. Compared to placebo, taranabant 2-8 mg was associated with an increased incidence of psychiatric-related adverse events (e.g., depression, 8.2% versus 2.5%, P = 0.048), gastrointestinal-related adverse events (e.g., nausea, 49.7% versus 19.0%, P < 0.001), and flushing/hot flash adverse events (10.7% versus 1.9%, P = 0.002).. Taranabant 2-8 mg did not improve smoking cessation and was associated with increased incidences of psychiatric-related, gastrointestinal-related, and flushing adverse events (ClinicalTrials.gov NCT00109135).

Topics: Adolescent; Adult; Aged; Amides; Behavior, Addictive; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Drug Inverse Agonism; Female; Humans; Male; Middle Aged; Pyridines; Receptor, Cannabinoid, CB1; Smoking Cessation; Tobacco Use Disorder

To evaluate the weight loss efficacy, safety and tolerability of taranabant, a CB1R inverse agonist, in obese and overweight patients.. Multicenter, double-blind, randomized, placebo-controlled study.. Patients >or=18 years old, BMI 27-43 kg m(-2), were randomized to placebo (n=209) or taranabant 0.5 mg (n=207), 1 mg (n=208) or 2 mg given orally once daily (n=417) for 52 weeks.. Key efficacy measurements included body weight (BW), waist circumference (WC), lipid endpoints and glycemic endpoints.. Based on a last observation carried forward analysis of the all-patients-treated population, mean change in BW for taranabant 0.5, 1, and 2 mg and placebo was -5.4, -5.3, -6.7 and -1.7 kg, respectively (P<0.001 for all doses vs placebo). The proportions of patients who lost at least 5 and 10% of their baseline BW at week 52 were significantly higher for all taranabant doses vs placebo (P<0.001 for all doses). Reductions in WC, percentage of body fat, and triglycerides were significant for taranabant 2 mg and in triglycerides for taranabant 1 mg vs placebo. There was no effect of taranabant vs placebo on other lipid or glucose-related endpoints. Incidences of adverse experiences classified in the gastrointestinal (diarrhea and nausea), nervous system (dizziness/dizziness postural), psychiatric-related (irritability and anger/aggression) and vascular (flushing/hot flush) organ systems were higher and statistically significant in the taranabant 2-mg group compared with the placebo group. Irritability was higher and statistically significant in all taranabant groups compared with the placebo group.. All three doses of taranabant-induced clinically meaningful and statistically significant weight loss. Incidences of adverse experiences in organ systems known to express CB1R were higher in taranabant groups.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amides; Anti-Obesity Agents; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Obesity; Pyridines; Receptor, Cannabinoid, CB1; Surveys and Questionnaires; Weight Loss; Young Adult

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.

Topics: Aminoimidazole Carboxamide; Animals; Body Weight; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred C57BL; Molecular Structure; Pyrazoles; Receptor, Cannabinoid, CB1; Stereoisomerism; Structure-Activity Relationship

This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.

Topics: Animals; Anti-Obesity Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Binding, Competitive; Body Weight; Cell Line; Cricetinae; Cricetulus; Crystallography, X-Ray; Dogs; Drug Inverse Agonism; Eating; Ether-A-Go-Go Potassium Channels; Glucuronides; Haplorhini; Hepatocytes; Humans; Mice; Mice, Knockout; Models, Molecular; Molecular Conformation; Pyrans; Pyridines; Rats; Receptor, Cannabinoid, CB1; Stereoisomerism; Structure-Activity Relationship

The endocannabinoid system plays a crucial role in the pathophysiology of obesity. However, the clinical use of cannabinoid antagonists has been recently stopped because of its central side-effects. The aim of this study was to compare the effects of a chronic treatment with the CB(1) cannabinoid antagonist rimonabant or the CB(1) inverse agonist taranabant in diet-induced obese female rats to clarify the biological consequences of CB(1) blockade at central and peripheral levels. As expected, chronic treatment with rimonabant and taranabant reduced body weight and fat content. Interestingly, a decrease in the number of CB(1) receptors and its functional activity was observed in all the brain areas investigated after chronic taranabant treatment in both lean and obese rats. In contrast, chronic treatment with rimonabant did not modify the density of CB(1) cannabinoid receptor binding, and decreased its functional activity to a lower degree than taranabant. Six weeks after rimonabant and taranabant withdrawal, CB(1) receptor density and activity recovered to basal levels. These results reveal differential adaptive changes in CB(1) cannabinoid receptors after chronic treatment with rimonabant and taranabant that could be related to the central side-effects reported with the use of these cannabinoid antagonists.

Topics: Amides; Analysis of Variance; Animals; Autoradiography; Benzoxazines; Body Weight; Brain; Cyclohexanols; Diet Fads; Disease Models, Animal; Eating; Female; Guanosine 5'-O-(3-Thiotriphosphate); International Cooperation; Morpholines; Naphthalenes; Obesity; Piperidines; Protein Binding; Pyrazoles; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Sulfur Isotopes; Time Factors; Tomography Scanners, X-Ray Computed; Tritium; Whole Body Imaging

Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demonstrating the positive modulation of food intake by the CB1 antagonist, rimonabant (3) (SR141716A). In the present study, various diaryl-pyrazole derivatives containing cycloalkyl building blocks were synthesized and tested for CB1 receptor binding affinities. Thorough structure-activity relationship (SAR) studies to optimize the pyrazole substituents led to several novel CB1 antagonists with K(i)

Topics: Animals; Anti-Obesity Agents; Body Weight; Cattle; Drug Design; Eating; Humans; Lipids; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

The application of the evolutionary fragment-based de novo design tool TOPology Assigning System (TOPAS), starting from a known CB1R (CB-1 receptor) ligand, followed by further refinement principles, including pharmacophore compliance, chemical tractability, and drug likeness, allowed the identification of benzodioxoles as a novel CB1R inverse agonist series. Extensive multidimensional optimization was rewarded by the identification of promising lead compounds, showing in vivo activity. These compounds reversed the CP-55940-induced hypothermia in Naval Medical Research Institute (NMRI) mice and reduced body-weight gain, as well as fat mass, in diet-induced obese Sprague-Dawley rats. Herein, we disclose the tools and strategies that were employed for rapid hit identification, synthesis and generation of structure-activity relationships, ultimately leading to the identification of (+)-[( R)-2-(2,4-dichloride-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone ( R)-14g . Biochemical, pharmacokinetic, and pharmacodynamic characteristics of ( R)-14g are discussed.

Topics: Animals; Anti-Obesity Agents; Benzodioxoles; Body Weight; Crystallography, X-Ray; Cyclohexanols; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Humans; Hypothermia; Ligands; Male; Mice; Microsomes; Models, Molecular; Molecular Structure; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Structure-Activity Relationship

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance. To explore the pharmacological utility of CB1R inhibition for the treatment of obesity, we evaluated the efficacy of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-[[5-(trifluoromethyl)pyridin-2-yl]oxy]propanamide (MK-0364) and determined the relationship between efficacy and brain CB1R occupancy in rodents. MK-0364 was shown to be a highly potent CB1R inverse agonist that inhibited the binding and functional activity of various agonists with a binding K(i) of 0.13 nM for the human CB1R in vitro. MK-0364 dose-dependently inhibited food intake and weight gain, with an acute minimum effective dose of 1 mg/kg in diet-induced obese (DIO) rats. CB1R mechanism-based effect was demonstrated for MK-0364 by its lack of efficacy in CB1R-deficient mice. Chronic treatment of DIO rats with MK-0364 dose-dependently led to significant weight loss with a minimum effective dose of 0.3 mg/kg (p.o.), or a plasma C(max) of 87 nM. Weight loss was accompanied by the loss of fat mass. Partial occupancy (30-40%) of brain CB1R by MK-0364 was sufficient to reduce body weight. The magnitude of weight loss was correlated with brain CB1R occupancy. The partial receptor occupancy requirement for efficacy was also consistent with the reduced food intake of the heterozygous mice carrying one disrupted allele of CB1R gene compared with the wild-type mice. These studies demonstrated that MK-0364 is a highly potent and selective CB1R inverse agonist and that it is orally active in rodent models of obesity.

Topics: Amides; Animals; Anti-Obesity Agents; Binding, Competitive; Body Temperature; Body Weight; CHO Cells; Colforsin; Cricetinae; Cricetulus; Cyclic AMP; Cyclohexanols; Dose-Response Relationship, Drug; Eating; Humans; Indoles; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Obesity; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Transfection

The discovery of novel acyclic amide cannabinoid-1 receptor inverse agonists is described. They are potent, selective, orally bioavailable, and active in rodent models of food intake and body weight reduction. A major focus of the optimization process was to increase in vivo efficacy and to reduce the potential for formation of reactive metabolites. These efforts led to the identification of compound 48 for development as a clinical candidate for the treatment of obesity.

Topics: Animals; Anti-Obesity Agents; Body Weight; Cannabinoids; Cyclic AMP; Eating; Humans; Liver; Microsomes; Obesity; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2