1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists for the treatment of obesity

Journal of Medicinal Chemistry

Volumn 52, Issue 8, 2009, Pages 2550-2558

  Vachal, Petr ^a   Fletcher, Joan M ^a   Fong, Tung M ^a   Huang, Cathy C R R ^a   Lao, Julie ^a   Xiao, Jing C ^a   Shen, C P ^a   Strack, Alison M ^a   Shearman, Lauren ^a   Stribling, Sloan ^a   Chen, Richard Z ^a   Frassetto, Andrea ^a   Tong, Xinchun ^a   Wang, Junying ^a   Ball, Richard G ^a   Tsou, Nancy N ^a   Hickey, Gerard J ^a   Thompson, Donald F ^a   Faidley, Terry D ^a   Nicolich, Susan ^a   Achanfuo Yeboah, Joana ^a   Hora, Donald F ^a   Hale, Jeffrey J ^a   Hagmann, William K ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 SULFONYL 4 ACYLPIPERAZINE DERIVATIVE; 4 (1,1 DIMETHYLHEPTYL) 1',2',3',4',5',6' HEXAHYDRO 2,3' DIHYDROXY 6' (3 HYDROXYPROPYL)BIPHENYL; CANNABINOID 1 RECEPTOR AGONIST; LIGAND; MK 0499; PIPERAZINE DERIVATIVE; RIMONABANT; SULFONE DERIVATIVE; TARANABANT; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; DOG; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG POTENCY; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN CELL; IN VIVO STUDY; MOLECULAR DOCKING; NONHUMAN; OBESITY; RAT; STRUCTURE ACTIVITY RELATION; WEIGHT REDUCTION; X RAY CRYSTALLOGRAPHY;

ANIMALS; ANTI-OBESITY AGENTS; BIOLOGICAL AVAILABILITY; BODY WEIGHT; DOGS; DRUG INVERSE AGONISM; EATING; HEPATOCYTES; HUMANS; MACACA MULATTA; MICROSOMES, LIVER; MODELS, MOLECULAR; PIPERAZINES; RATS; RECEPTOR, CANNABINOID, CB1; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES;

EID: 65449118439     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900063x     Document Type: Article

References (14)

1. Center of Disease Control Web site: http://www.cdc.gov/nchs /FASTATS/lcod.htm.
2. Morton, G. L.; Cummings, D. E.; Baskin, D. G.; Barsh, G. S.; Schwartz, M. W. Central nervous system control of food intake and body weight. Nature (London) 2006, 443 , 289-295.
3. (a) Di Marzo, V.; Goparaju, S. K.; Wang, L.; Liu, J.; Bitkai, S.; Jarai, Z.; Fezza, F.; Miura, G. I.; Palmiter, R. D.; Sugiura, T.; Kunos, G Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature (London) 2001, 410 , 822-825.
4. (b) Van Gaal, L. F.; Rissanen, A. M.; Scheen, A. J.; Ziegler, O.; Roessner, S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005, 365 , 1389-1397.
5. Rimonabant was approved for the treatment of obesity in the European Union in 2006. For more information, see http://en. sanofi-aventis.com /events/event1/en/about.asp.
6. Addy, C.; 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. 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. J. Clin. Pharmacol. 2008, 48 , 418-427.
7. For a detailed discussion of biological assays, see the following: Fong, T. M.; Guan, X.-M.; Marsh, D. J.; Shen, C.-P.; Stribling, D. S.; Rosko, K. M.; Lao, J.; Yu, H.; Feng, Y.; Xiao, J. C; Van der Ploeg, L. H. T.; Goulet, M. T.; Hagmann, W. K.; Lin, L. S.; Lanza, T. J.; Jewell, J. P.; Liu, P.; Shah, S. K.; Qi, H.; Tong, X.; Wang, J.; Xu, S. S.; Francis, B.; Strack, A. M.; MacIntyre, D. E.; Shearman, L. P. 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. J. Pharmacol. Exp. Ther. 2007, 321 , 1013-1022.
8. 2, 10 mM HEPES, pH 7.3, 1 mg/mL BSA) at room temperature for 30 min. Cells were lysed by boiling, and intracellular cAMP level was determined using the cAMP SPA kit (Amersham). When adenylyl cyclase is activated by forskolin, activation of Gi by CB1R in the presence of agonist (such as CP55940) will lead to an inhibition of the forskolin-stimulated cAMP increase, and inverse agonist will lead to a further increase of the forskolin-stimulated cAMP increase. The maximal CP55940-mediated inhibition of forskolin-stimulated cAMP increase is defined as 100% agonist efficacy, and the intrinsic activity of all other compounds is relative to the efficacy of CP55940. Negative efficacy denotes inverse agonism.
9. 50 values were calculated through nonlinear curve fitting.
10. Food intake assays. For automated food intake system, Sprague-Dawley CD and DIO (dietary-induced obese Sprague-Dawley CD) rats (obtained from Charles River Labs; Wilmington, DE) were caged individually in Nalgene cages with metabolism feeders attached to them. The food cups were external to the feeder and were placed on individual balances. Each balance was connected to a central computer that collects readings every 5 min to measure grams of food consumed. Rats were transferred into the AFIS for at least 3 days before the experiment to allow for acclimation. For overnight food intake (FI) and body weight (BW) assay, male DIO rats were orally gavaged at 1 h prior to dark cycle onset with vehicle (10% Tween-80 in water) or the CB1R inverse agonist. Rats were fed milled MHF diet during acclimation to the caging and during the experiment. Overnight food intake and body weight changes were measured. Significance level was set at P <0.05.
11. 2 analysis.
12. Corey, E. J.; Chaykovsky, M. Dimethyloxosulfonium methylide and dimethylsulfonium methylide. Formation and application to organic synthesis. J. Am. Chem. Soc. 1965, 87 , 1353-1364.
13. Mass Spectrometer: Micromass ZQ single quadrupole, electrospray positive ionization, full scan mode (150-750 amu in 0.5 s). HPLC: Agilent 1100, binary pump. DAD UV detector: hardware/software Waters/Micromass MassLynx 4.0. Column: Waters Xterra, 2.1 mm width, 20 mm length, 3.5 μm packing material. Run time: 4 min. Flow rate: 1.0 mL /min. Mobile phase A) water + 0.05% TFA. Mobile phase B) acetonitrile + 0.05% TFA. Gradient, time/% A/% B: 0.00 /95/05, 3.00/2/98, 3.25/2/98, 3.26/95/5, 4.00/95/5.
14. The final crude product 70 contains approximately 10% of tert-butyl 4-{3-[4- (trifluoromethyl) phenyl]butanoyl}piperazine-1-carboxylate byproduct which does not negatively affect the subsequent steps; E/Z ratio of 70 is>50/1.