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

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

Improving the maintenance of weight loss remains a critical challenge for obesity researchers. The present 1-year, randomized, placebo-controlled trial evaluated the safety and efficacy of weight maintenance counseling combined with either placebo or the cannabinoid-1 receptor inverse agonist, taranabant, for sustaining prior weight loss achieved on a low-calorie diet (LCD). Seven hundred eighty-four individuals who had lost ≥ 6% of body weight during six initial weeks of treatment with an 800 kcal/day liquid LCD were randomly assigned to placebo or once-daily taranabant in doses of 0.5, 1, or 2 mg. All participants were provided monthly, on-site behavioral weight maintenance counseling, as well as monthly phone calls. The primary end point was change in body weight from randomization to week 52. The randomized participants lost an average of 9.6 kg (9.5% of initial weight) during the 6-week LCD. The model-adjusted mean change in body weight during the subsequent 1 year was +1.7 kg for placebo, compared with -0.1, -0.6, and -1.2 kg for the taranabant 0.5, 1, and 2 mg doses, respectively (all P values ≤ 0.007 vs. placebo). The incidences of psychiatric-related adverse events, including irritability, were higher for taranabant 1 and 2 mg vs. placebo (P ≤ 0.038). In addition to reporting data on the safety and efficacy of taranabant, this study provides a method for studying the combination of lifestyle modification and pharmacotherapy for weight maintenance after diet-induced weight loss.

Topics: Adult; Amides; Anti-Obesity Agents; Combined Modality Therapy; Counseling; Diet, Reducing; Double-Blind Method; Female; Humans; Life Style; Male; Middle Aged; Obesity; Pyridines; Receptor, Cannabinoid, CB1; Weight Loss

To evaluate the efficacy and safety of taranabant in overweight and obese patients with type 2 diabetes mellitus (T2DM).. This was a multicenter, double-blind, randomized, placebo-controlled study in overweight and obese patients with T2DM (ages > or = 18 and < or = 75 years) with a BMI > or = 27 kg/m(2) and < or = 43 kg/m(2) and HbA1c > or =7.0 and < or = 10.0%, who were either not on an antihyperglycaemic agent or on a stable dose of metformin (> or = 1500 mg/day). After a 2-week placebo run-in, patients were randomized to placebo (N = 156) or taranabant 0.5-mg (N = 155), 1-mg (N = 157), or 2-mg (N = 155) once daily for 52 weeks. Primary efficacy endpoints were changes from baseline in body weight (BW) and HbA1c at Week 36, with results at Week 52 being key secondary endpoints.. In the all-patients-treated population, using a last-observation-carried-forward analysis, reductions in BW were -2.5, -3.7, -4.5 and -5.1 kg at Week 36 and -2.4, -4.0, -4.6 and -5.3 kg at Week 52 in the placebo, 0.5-, 1- and 2-mg groups, respectively (all doses significant vs. placebo at both time points). The proportion of patients who lost > or = 5 and > or = 10% of their baseline BW was significantly greater in the 1- and 2-mg groups vs. placebo at Week 36 and all taranabant groups vs. placebo at Week 52. Reductions in HbA1c were -0.40, -0.47, -0.68 and -0.71% at Week 36 and -0.30, -0.43, -0.65 and -0.64% at Week 52, in the placebo, 0.5-, 1- and 2-mg groups, respectively (1- and 2-mg doses significant vs. placebo at both time points). After 52 weeks, the incidences of adverse experiences classified in the gastrointestinal (diarrhoea, nausea, vomiting), nervous system-related (dizziness, sensory-related), and psychiatric (irritability, depression-related) organ systems were numerically higher or statistically significantly higher in all taranabant groups compared with the placebo group.. After 36 and 52 weeks, treatment with taranabant at the 1- and 2-mg doses led to clinically significant weight loss and improvement in glycaemic parameters in overweight and obese patients with T2DM that was associated with dose-related increases in adverse experiences. Based on these data and data from other Phase III clinical studies, it was determined that the overall safety and efficacy profile of taranabant did not support further development for the treatment of obesity.

Topics: Adolescent; Adult; Aged; Amides; Anti-Obesity Agents; Body Mass Index; Diabetes Mellitus, Type 2; Diet, Reducing; Double-Blind Method; Female; Humans; Male; Middle Aged; Obesity; Pyridines; Receptor, Cannabinoid, CB1; Weight Loss; Young Adult

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.

Topics: Adult; Aged; Amides; Brain; Dose-Response Relationship, Drug; Double-Blind Method; Energy Intake; Energy Metabolism; Fats; Humans; Middle Aged; Positron-Emission Tomography; Pyridines; Receptor, Cannabinoid, CB1; Weight Loss

Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.

Topics: Administration, Oral; Animals; Eating; Humans; Naphthyridines; Pharmacokinetics; Pyridines; Rats; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Structure-Activity Relationship; Weight Loss

Interaction studies with digoxin (Lanoxin; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant--a cannabinoid-1 receptor inverse agonist--for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction.. This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day -14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued.. The geometric mean ratio and 90% confidence intervals for digoxin AUC(0-infinity) were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C(max)) were 1.23 (1.09, 1.40). The median time to C(max) was the same for both treatments.. Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

Topics: Administration, Oral; Adult; Amides; Analysis of Variance; Area Under Curve; Cardiotonic Agents; Digoxin; Dose-Response Relationship, Drug; Drug Evaluation; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Half-Life; Humans; Least-Squares Analysis; Linear Models; Male; Middle Aged; Pyridines; Safety; Weight Loss