686344-50-3Relevant academic research and scientific papers
Functionalized 6-(Piperidin-1-yl)-8,9-Diphenyl Purines as Peripherally Restricted Inverse Agonists of the CB1 Receptor
Amato, George,Manke, Amruta,Wiethe, Robert,Vasukuttan, Vineetha,Snyder, Rodney,Yueh, Yun Lan,Decker, Ann,Runyon, Scott,Maitra, Rangan
, p. 6330 - 6345 (2019/07/03)
Peripherally restricted CB1 receptor antagonists may be useful in treating metabolic syndrome, diabetes, liver diseases, and gastrointestinal disorders. Clinical development of the centrally acting CB1 inverse agonist otenabant (1) was halted due to its p
Functionalized 6-(piperidin-1-yl)-8,9-diphenyl purines as inverse agonists of the CB1 receptor – SAR efforts towards selectivity and peripheralization
Amato, George,Wiethe, Robert,Manke, Amruta,Vasukuttan, Vineetha,Snyder, Rodney,Runyon, Scott,Maitra, Rangan
, p. 3632 - 3649 (2019/07/12)
Antagonists of type 1 cannabinoid receptors (CB1) may be useful in treating diabetes, hepatic disorders, and fibrosis. Otenabant (1) is a potent and selective CB1 inverse agonist that was under investigation as an anti-obesity agent, but its development was halted once adverse effects associated with another marketed inverse agonist rimonabant (2) became known. Non-tissue selective antagonists of CB1 that have high levels of brain penetration produce adverse effects in a small subset of patients including anxiety, depression and suicidal ideation. Currently, efforts are underway to produce compounds that have limited brain penetration. In this report, novel analogs of 1 are explored to develop and test strategies for peripheralization. The piperidine of 1 is studied as a linker, which is functionalized with alkyl, heteroalkyl, aryl and heteroaryl groups using a connector in the form of an amine, amide, sulfonamide, sulfamide, carbamate, oxime, amidine, or guanidine. We also report more polar replacements for the 4-chlorophenyl group in the 9-position of the purine core, which improve calculated physical properties of the molecules. These studies resulted in compounds such as 75 that are potent inverse agonists of hCB1 with exceptional selectivity for hCB1 over hCB2. SAR studies revealed ways to adjust physical properties to limit brain exposure.
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
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.
supporting information; experimental part, p. 234 - 237 (2009/09/25)
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.
PURINE COMPOUNDS AND USES THEREOF AS CANNABINOID RECEPTOR LIGANDS
-
Page 67-68, (2008/06/13)
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.
