Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), in Rodents

  title={Antiobesity Efficacy of a Novel Cannabinoid-1 Receptor Inverse Agonist, N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-\{[5-(trifluoromethyl)pyridin-2-yl]oxy\}propanamide (MK-0364), in Rodents},
  author={Tung Ming Fong and Xiao-ming Guan and Donald J. Marsh and Chun-Pyn Shen and D. Sloan Stribling and Kim Rosko and Julie Z. Lao and Hong Yu and Yue Feng and Jing Chen Xiao and Lex H. T. van der Ploeg and Mark T. Goulet and William K. Hagmann and Linus Shouzhong Lin and Thomas J. Lanza and James P. Jewell and Ping-Hua Liu and Shrenik K. Shah and Hongbo Qi and Xinchun S Tong and Junying Wang and Suoyu S. Xu and Barbara Francis and Alison M. Strack and D. Euan Macintyre and Lauren P. Shearman},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={1013 - 1022}
  • T. Fong, X. Guan, L. Shearman
  • Published 1 June 2007
  • Biology, Chemistry, Medicine
  • Journal of Pharmacology and Experimental Therapeutics
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… 
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) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity.
Although pyrazole 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.
Metabolism and excretion of [14C]taranabant, a cannabinoid-1 inverse agonist, in humans
The data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.
In vitro and in vivo metabolism of a novel cannabinoid-1 receptor inverse agonist, taranabant, in rats and monkeys
Major pathways of metabolism that were common to rats and rhesus monkeys included hydroxylation at the benzylic carbon adjacent to the cyanophenyl ring to form a biologically active circulating metabolite M1, and oxidation of one of the two geminal methyl groups of taranabant or M1 to the corresponding diastereomeric carboxylic acids.
Quantitative in vitro and in vivo pharmacological profile of CE-178253, a potent and selective cannabinoid type 1 (CB1) Receptor Antagonist
Evaluating the quantitative pharmacology and concentration/effect relationships of CE-178253 based on unbound plasma concentration and in vitro pharmacology data in different in vivo preclinical models of FI and energy expenditure suggested that a greater than a 2-fold coverage of the Ki is required for maximum efficacy.
Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity.
Four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding are identified, including trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
Benzodioxoles: novel cannabinoid-1 receptor inverse agonists for the treatment of obesity.
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, allowed the identification of benzodioxoles as a novelCB1R inverse agonist series, showing in vivo activity.
Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists.
  • R. Pertwee
  • Biology, Chemistry
    Current medicinal chemistry
  • 2010
This review describes what is currently known about the ability of such compounds to bind to, activate, inhibit or block non-CB(1), non- CB(2) G protein-coupled receptors such as GPR55, transmitter gated channels, ion channels and nuclear receptors in an orthosteric or allosteric manner.


Discovery of N-[(1S,2S)-3-(4-Chlorophenyl)-2- (3-cyanophenyl)-1-methylpropyl]-2-methyl-2- {[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide (MK-0364), a novel, acyclic cannabinoid-1 receptor inverse agonist for the treatment of obesity.
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
Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists.
Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.
Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.
It is concluded that anandamide acting at hepatic CB(1) contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats
The occupancy method described here is an effective tool for interrelating central CB1 receptor occupancy with neurobiological actions ofCB1 receptor antagonists and for furthering the understanding of the role of CB1 receptors in central nervous system physiology and pathology.
Pharmacological profile of a series of bicyclic cannabinoid analogs: classification as cannabimimetic agents.
The goals of the studies described herein were to determine whether these bicyclic analogs possess similar pharmacological properties of delta 9-THC, to compare pharmacological activity after s.c. and i.v. administration, and to evaluate the structure-activity relationship of this series of analogs for further insight into cannabinoid mechanism of action.
Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding
Observational analysis of feeding induced by Δ9-THC and anandamide
Observational analysis of feeding induced by Delta9-THC and anandamide.
The data suggest that exogenously administered cannabinoids promote eating by increasing the incentive value of food and support a role for endocannabinoids in the regulation of the appetitive aspects of feeding motivation.
A Selective Inverse Agonist for Central Cannabinoid Receptor Inhibits Mitogen-activated Protein Kinase Activation Stimulated by Insulin or Insulin-like Growth Factor 1
Chinese hamster ovary cells transfected with human central cannabinoid receptor (CB1) exhibit high constitutive activity at both levels of mitogen-activated protein kinase (MAPK) and adenylyl cyclase, and the CB1-selective ligand, SR 141716A, that functions as an inverse agonist is proposed as a novel model for receptor/ligand interactions.