The Experts below are selected from a list of 21948 Experts worldwide ranked by ideXlab platform
Tung M Fong - One of the best experts on this subject based on the ideXlab platform.
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dihydro pyrano 2 3 b pyridines and tetrahydro 1 8 naphthyridines as cb1 Receptor inverse agonists synthesis sar and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Christina B Madsenduggan, John S Debenham, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Thomas F Walsh, Lin Yan, Pei Huo, Jing Chen XiaoAbstract: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.
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cb1 Receptor inverse agonist pharmacotherapy for metabolic disorders
Drug Development Research, 2009Co-Authors: Carol Addy, Tung M Fong, Ngozi Erondu, Steven B HeymsfieldAbstract:The Cannabinoid-1 Receptor (CB1R) has been implicated in the control of energy balance based on its anatomical localization, the interaction among the endoCannabinoid system and other transmitter systems, and the appetite-enhancing effect of tetrahydrocannabinol. Recent development of CB1R inverse agonists indicated that these agents inhibit food intake, increase energy expenditure, and reduce fat mass. This article reviews the preclinical and clinical efficacy of several CB1R inverse agonists and provides a perspective on the use of CB1R inverse agonists in studies of obesity and metabolic disorders. The compounds reviewed here are no longer in clinical development for obesity. Drug Dev Res 70:566–576, 2009. © 2009 Wiley-Liss, Inc.
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pyridopyrimidine based Cannabinoid 1 Receptor inverse agonists synthesis and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: John S Debenham, Christina B Madsenduggan, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Marietherese Schaeffer, Jing Chen Xiao, Cathy C R R Huang, Chunpyn ShenAbstract:The synthesis, SAR and binding affinities are described for Cannabinoid-1 Receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Tung M Fong, Jing Chen Xiao, Chunpyn Shen, Xiaoming Guan, Donald J Marsh, Sloan D Stribling, Kim Rosko, Julie Z Lao, Yue Feng, Lex H T Van Der PloegAbstract: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 -[(1 S ,2 S )-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.
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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
Journal of Medicinal Chemistry, 2006Co-Authors: Linus S Lin, Junying Wang, Xinchun Tong, Tung M Fong, Chunpyn Shen, Ping Liu, Thomas J Lanza, James P Jewell, Shrenik K Shah, Julie LaoAbstract: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.
Chunpyn Shen - One of the best experts on this subject based on the ideXlab platform.
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pyridopyrimidine based Cannabinoid 1 Receptor inverse agonists synthesis and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: John S Debenham, Christina B Madsenduggan, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Marietherese Schaeffer, Jing Chen Xiao, Cathy C R R Huang, Chunpyn ShenAbstract:The synthesis, SAR and binding affinities are described for Cannabinoid-1 Receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Tung M Fong, Jing Chen Xiao, Chunpyn Shen, Xiaoming Guan, Donald J Marsh, Sloan D Stribling, Kim Rosko, Julie Z Lao, Yue Feng, Lex H T Van Der PloegAbstract: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 -[(1 S ,2 S )-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.
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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
Journal of Medicinal Chemistry, 2006Co-Authors: Linus S Lin, Junying Wang, Xinchun Tong, Tung M Fong, Chunpyn Shen, Ping Liu, Thomas J Lanza, James P Jewell, Shrenik K Shah, Julie LaoAbstract: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.
Julie Lao - One of the best experts on this subject based on the ideXlab platform.
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dihydro pyrano 2 3 b pyridines and tetrahydro 1 8 naphthyridines as cb1 Receptor inverse agonists synthesis sar and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Christina B Madsenduggan, John S Debenham, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Thomas F Walsh, Lin Yan, Pei Huo, Jing Chen XiaoAbstract: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.
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pyridopyrimidine based Cannabinoid 1 Receptor inverse agonists synthesis and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: John S Debenham, Christina B Madsenduggan, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Marietherese Schaeffer, Jing Chen Xiao, Cathy C R R Huang, Chunpyn ShenAbstract:The synthesis, SAR and binding affinities are described for Cannabinoid-1 Receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
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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
Journal of Medicinal Chemistry, 2006Co-Authors: Linus S Lin, Junying Wang, Xinchun Tong, Tung M Fong, Chunpyn Shen, Ping Liu, Thomas J Lanza, James P Jewell, Shrenik K Shah, Julie LaoAbstract: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.
Lex H T Van Der Ploeg - One of the best experts on this subject based on the ideXlab platform.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Tung M Fong, Jing Chen Xiao, Chunpyn Shen, Xiaoming Guan, Donald J Marsh, Sloan D Stribling, Kim Rosko, Julie Z Lao, Yue Feng, Lex H T Van Der PloegAbstract: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 -[(1 S ,2 S )-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.
Jing Chen Xiao - One of the best experts on this subject based on the ideXlab platform.
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dihydro pyrano 2 3 b pyridines and tetrahydro 1 8 naphthyridines as cb1 Receptor inverse agonists synthesis sar and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2010Co-Authors: Christina B Madsenduggan, John S Debenham, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Thomas F Walsh, Lin Yan, Pei Huo, Jing Chen XiaoAbstract: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.
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pyridopyrimidine based Cannabinoid 1 Receptor inverse agonists synthesis and biological evaluation
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: John S Debenham, Christina B Madsenduggan, Junying Wang, Xinchun Tong, Julie Lao, Tung M Fong, Marietherese Schaeffer, Jing Chen Xiao, Cathy C R R Huang, Chunpyn ShenAbstract:The synthesis, SAR and binding affinities are described for Cannabinoid-1 Receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
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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
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Tung M Fong, Jing Chen Xiao, Chunpyn Shen, Xiaoming Guan, Donald J Marsh, Sloan D Stribling, Kim Rosko, Julie Z Lao, Yue Feng, Lex H T Van Der PloegAbstract: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 -[(1 S ,2 S )-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.
