Taranabant


CAS No. : 701977-09-5

Taranabant,701977-09-5
Product Details
For research use only. Not Intended for Therapeutic Use!
Cat No:I004634
Synonyms:N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxypropanamide
Molecular Formula:C27H25ClF3N3O2
Molecular Weight:516.0
Target:Cannabinoid Receptor
IC50:0.3 nM(binding affinity)
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Appearance:Solid powder
Purity: > 98%
Cat No:I004634
Cas No:701977-09-5
Product-Name:Taranabant
IUPAC Name:N-[(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)butan-2-yl]-2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]oxypropanamide
InChI:InChI=1S/C27H25ClF3N3O2/c1-17(34-25(35)26(2,3)36-24-12-9-21(16-33-24)27(29,30)31)23(14-18-7-10-22(28)11-8-18)20-6-4-5-19(13-20)15-32/h4-13,16-17,23H,14H2,1-3H3,(H,34,35)/t17-,23+/m0/s1
InChIKey:QLYKJCMUNUWAGO-GAJHUEQPSA-N
SMILES:CC(C(CC1=CC=C(C=C1)Cl)C2=CC=CC(=C2)C#N)NC(=O)C(C)(C)OC3=NC=C(C=C3)C(F)(F)F

Taranabant(cas 701977-09-5) also known as MK 0364, is a cannabinoid 1 receptor inverse agonist with IC50 of 0.3 nM. Taranabant is a cannabinoid receptor type 1 inverse agonist being investigated as a potential treatment for obesity due to its anorectic effects. Treatment with taranabant 0.5-, 1- and 2-mg led to significant reductions in FPG at Weeks 36 and 52. There were no significant differences in fasting serum insulin concentrations at Weeks 36 or 52. Statistically significant improvements in insulin sensitivity (QUICKI) were seen with taranabant 0.5- and 2-mg at Week 36 but not at Week 52.

Originator: Merck & Co
Class: Amides; Obesity therapies; Pyridines
Mechanism of Action: Cannabinoid 1 receptor inverse agonists Orphan Drug Status: No
New Molecular Entity: Yes
1. J Clin Pharmacol. 2008 Jun;48(6):734-44. doi: 10.1177/0091270008317591.
Multiple-dose pharmacokinetics, pharmacodynamics, and safety of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, in healthy male volunteers.
Addy C(1), Rothenberg P, Li S, Majumdar A, Agrawal N, Li H, Zhong L, Yuan J, Maes A, Dunbar S, Cote J, Rosko K, Van Dyck K, De Lepeleire I, de Hoon J, Van Hecken A, Depré M, Knops A, Gottesdiener K, Stoch A, Wagner J.
Author information:
(1)Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115, USA. carol_addy@merck.com
Taranabant is a cannabinoid-1 receptor inverse agonist for the treatment of obesity. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of taranabant (5, 7.5, 10, or 25 mg once daily for 14 days) in 60 healthy male subjects. Taranabant was rapidly absorbed, with a median t(max) of 1.0 to 2.0 hours and a t(1/2) of approximately 74 to 104 hours. Moderate accumulation was observed in C(max) (1.18- to 1.40-fold) and AUC(0-24 h) (1.5- to 1.8-fold) over 14 days for the 5-, 7.5-, and 10-mg doses, with an accumulation half-life ranging from 15 to 21 hours. Steady state was reached after 13 days. After multiple-dose administration, plasma AUC(0-24 h) and C(max) of taranabant increased dose proportionally (5-10 mg) and increased somewhat less than dose proportionally for 25 mg. Taranabant was generally well tolerated up to doses of 10 mg and exhibited multiple-dose pharmacokinetics consistent with once-daily dosing.

2. J Med Chem. 2008 Apr 10;51(7):2108-14. doi: 10.1021/jm7014974. Epub 2008 Mar 12.
Conformational analysis and receptor docking of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(t rifluoromethyl)pyridin-2-yl]oxy}propanamide (taranabant, MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist.
Lin LS(1), Ha S, Ball RG, Tsou NN, Castonguay LA, Doss GA, Fong TM, Shen CP, Xiao JC, Goulet MT, Hagmann WK.
Author information:
(1)Departments of Medicinal Chemistry, Molecular Systems, Process Research, and Metabolic Disorders, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
X-ray crystallographic, NMR spectroscopic, and computational studies of taranabant afforded similar low-energy conformers with a significant degree of rigidity along the C11-N13-C14-C16-C17 backbone but with more flexibility around bonds C8-C11 and C8-O7. Mutagenesis and docking studies suggested that taranabant and rimonabant shared the same general binding area of CB1R but with significant differences in detailed interactions. Similar to rimonabant, taranabant interacted with a cluster of aromatic residues (F(3.36)200, W(5.43)279, W(6.48)356, and Y(5.39)275) through the two phenyl rings and with F(2.57)170 and L(7.42)387 through the CF 3-Pyr ring. The notable distinction between taranabant and rimonabant was that taranabant was hydrogen-bonded with S(7.39)383 but not with K(3.28)192, while rimonabant was hydrogen-bonded with K(3.28)192 but not with S(7.39)383. The strong hydrogen bonding between the amide NH of taranabant and hydroxyl of S(7.39)383 was key to the superior affinity of taranabant to CB1R.

3. J Clin Pharmacol. 2008 Apr;48(4):418-27. doi: 10.1177/0091270008314467. Epub 2008 Feb 7.
Safety, tolerability, pharmacokinetics, and pharmacodynamic properties of taranabant, a novel selective cannabinoid-1 receptor inverse agonist, for the treatment of obesity: results from a double-blind, placebo-controlled, single oral dose study in healthy volunteers.
Addy C(1), Li S, Agrawal N, Stone J, Majumdar A, Zhong L, Li H, Yuan J, Maes A, Rothenberg P, Cote J, Rosko K, Cummings C, Warrington S, Boyce M, Gottesdiener K, Stoch A, Wagner J.
Author information:
(1)Clinical Pharmacology, Merck Research Laboratories, 33 Avenue Louis Pasteur, HB3-429, Boston, MA 02115, USA. carol_addy@merck.com
Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers. Single-dose AUC(0-infinity) and C(max) values for taranabant increased approximately linearly with dose up to 200 mg, with slightly less than dose-proportional increases in AUC(0-infinity) and C(max) values for doses >200 mg. Plasma taranabant had a biphasic disposition, with a median t(max) of 1 to 2.5 hours and a terminal elimination t((1/2)) of 38 to 69 hours. Coadministration of taranabant with a high-fat meal led to a 14% increase in C(max) and a 74% increase in AUC(0-infinity). Clinical adverse experiences associated with single doses of taranabant were generally mild and transient. Of the 198 clinical adverse experiences reported, the most common drug-related ones were nausea (36), headache (22), drowsiness (14), abdominal discomfort/abdominal pain/stomachache (14), hiccups (9), dizziness (8), decreased appetite (7), increased bowel movement (7), mood change (6), tiredness (4), vomiting (4), and sweating increased (4). Taranabant has pharmacokinetic characteristics suitable for a once-daily dosing regimen.

4. Cell Metab. 2008 Jan;7(1):68-78. doi: 10.1016/j.cmet.2007.11.012.
The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake.
Addy C(1), Wright H, Van Laere K, Gantz I, Erondu N, Musser BJ, Lu K, Yuan J, Sanabria-Bohórquez SM, Stoch A, Stevens C, Fong TM, De Lepeleire I, Cilissen C, Cote J, Rosko K, Gendrano IN 3rd, Nguyen AM, Gumbiner B, Rothenberg P, de Hoon J, Bormans G, Depré M, Eng WS, Ravussin E, Klein S, Blundell J, Herman GA, Burns HD, Hargreaves RJ, Wagner J, Gottesdiener K, Amatruda JM, Heymsfield SB.
Author information:
(1)Merck Research Laboratories, Boston, MA 02115, USA.
Comment in
Cell Metab. 2008 Jan;7(1):1-2.
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.
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