- Discovery of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4- ethylamino-piperidine-4-carboxylic Acid Amide Hydrochloride (CP-945,598), a novel, potent, and selective cannabinoid type 1 receptor antagonist
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We report the structure-activity relationships, design, and synthesis of the novel cannabinoid type 1 (CB1) receptor antagonist 3a (CP-945,598). Compound 3a showed subnanomolar potency at human CB1 receptors in binding (Ki= 0.7 nM) and functional assays (K i = 0.12 nM). In vivo, compound 3a reversed cannabinoid agonist-mediated responses, reduced food intake, and increased energy expenditure and fat oxidation in rodents. The endocannabinoid system (ECS a), and speci?cally the cannabinoid type 1 (CB1) receptor, plays a pivotal role in energy homeostasis.1-3 As such, stimulation of the ECS promotes food intake and energy storage and may be chronically overactive in obese subjects.4-7 In contrast, blockade of the CB 1 receptor decreases food intake and increases energy expenditure, leading to a reduction in body weight.8-11 It was hoped that CB 1 ceptor antagonists might provide effective therapy options for the management of metabolic disorders, such as obesity. Unfortunately, several CB1 receptor inverse agonists/antagonists were recently withdrawn from clinical development including the diarylpyrazole rimonabant12 1 (SR141716A) and the acyclic amide taranabant132 (MK-0364). Herein, we describe the design strategies that led to the identi?cation of a series of purine derivatives as CB1 receptor antagonists, and the optimization of PK properties that resulted in the discovery of the orally active 3a (CP-945,598), a novel, potent, and selective CB1 receptor antagonist, recently evaluated in phase 3 clinical trials for weight management.
- Griffith, David A.,Hadcock, John R.,Black, Shawn C.,Iredale, Philip A.,Carpino, Philip A.,Dasilva-Jardine, Paul,Day, Robert,Dibrino, Joseph,Dow, Robert L.,Landis, Margaret S.,O'Connor, Rebecca E.,Scott, Dennis O.
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supporting information; experimental part
p. 234 - 237
(2009/09/25)
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- New bicyclic cannabinoid receptor-1 (CB1-R) antagonists
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A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB1-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-
- Carpino, Philip A.,Griffith, David A.,Sakya, Subas,Dow, Robert L.,Black, Shawn C.,Hadcock, John R.,Iredale, Philip A.,Scott, Dennis O.,Fichtner, Michael W.,Rose, Colin R.,Day, Robert,Dibrino, Joseph,Butler, Mary,DeBartolo, Demetria B.,Dutcher, Darrin,Gautreau, Denise,Lizano, Jeff S.,O'Connor, Rebecca E.,Sands, Michelle A.,Kelly-Sullivan, Dawn,Ward, Karen M.
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p. 731 - 736
(2007/10/03)
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- BICYCLIC IMIDAZOLYL PYRIMIDIN-4-ONE CANNABINOID RECEPTOR LIGANDS AND USES THEREOF
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Compounds of Formula (I) are described herein. The compounds have been shown to act as cannabinoid receptor ligands and are therefore useful in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals.
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Page/Page column 47-48
(2010/02/12)
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- PURINE COMPOUNDS AND USES THEREOF AS CANNABINOID RECEPTOR LIGANDS
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Compounds of Formula (I) that act as cannabinoid receptor ligands and their uses in the treatment of diseases linked to the mediation of the cannabinoid receptors in animals are described herein.
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