Novel thioamide derivatives as neutral CB1 receptor antagonists

Boström, Jonas; Olsson, Roine I.; Tholander, Joakim; Greasley, Peter J.; Ryberg, Erik; Nordberg, Henrik; Stephan, Holger; Cheng, Lan

doi:10.1016/j.bmcl.2009.11.125

Cited by 25 publications

(16 citation statements)

References 16 publications

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“…However, AM4113 produces anxiety‐like effects similar to that seen with rimonabant in an open field assay (75). More recently, a novel class of CB1 receptor neutral‐antagonist thioamide derivatives have shown efficacy at reducing food intake (61), but the adverse effect profile is currently unknown. Lastly, there is increasing debate as to whether it is feasible for a ligand to behave as a true neutral antagonist in a living system (76,77), and those interested in this discussion as it pertains to CB1 receptor antagonists should see ref.…”

Section: “Neutral Antagonists”mentioning

confidence: 99%

“…Recently, a structural series of novel thioamide derivatives having CB1 receptor antagonist activity was reported by AstraZeneca (61). The compounds are synthesized by the exchange of a thioamide linker for the carboxamide linker in 5,6‐diaryl‐pyrazine‐2‐amide derivatives, an exchange that maintains the proposed bioactive conformation.…”

Section: Introductionmentioning

confidence: 99%

“…These compounds reduce the body weight of cafeteria diet‐induced obese mice, an effect that remains even after a 1–2 week washout period. The anorectic effect of these compounds is believed to be due to neutral‐antagonist properties (61).…”

Section: Introductionmentioning

confidence: 99%

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Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Ward

Raffa

2011

Obesity

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Section: “Neutral Antagonists”mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Ward

Raffa

2011

Obesity

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“…Other classes of CB1R regulators in the form of neutral antagonists, that do not change basal CB1R activity, have been revealed (Pan et al, 1998) and are the subject of study (Hurst et al, 2002, 2006; Pertwee, 2005a; Reggio, 2009; Silvestri & Di Marzo, 2012) and development (Alonso et al, 2012; Argueta & DiPatrizio, 2017; Bostroem et al, 2010; Brents et al, 2012; Franks et al, 2014; Fride et al, 2007; Greig & Ross, 2010; Kangas et al, 2013; Makriyannis & Vemuri, 2008; Ruiu et al, 2003; Vela Hernandez & Yenes Minguez, 2009; Wargent et al, 2013; Wiley et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Metabolic Profiling of CB1 Neutral Antagonists

Seltzman

Maitra

Bortoff³

et al. 2017

Methods in Enzymology

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PIMSR is among the first neutral antagonists for the CB1R and was demonstrated pharmacologically to bind to the CB1R, yet not alter calcium flux. It was further shown computationally to be able to stabilize both the active and inactive states of CB1R revealing the molecular interactions that mechanistically afford the property of neutral antagonism. PIMSR shows dramatic positive effects in reducing weight, food intake, and adiposity as well as in improving glycemic control and lipid homeostasis in high-fat diet-induced obese mice, but also shows increased ALT and liver weight as markers of liver injury with chronic administration. Further, in a separate study, 3-day administration of PIMSR in C57BL/6J mice, hepatic steatosis from an acute administration of high of ethanol was significantly reduced. Also, it partially prevented alcohol-induced increases in ALT, AST, and LDH. The differences in ALT levels in obese and nonobese mice under different test paradigms are unlikely to be due to neutral antagonism itself since other neutral antagonists (AM6545) do not exhibit liver injury. The brain levels of low micromolar would support significant brain CB1 receptor occupancy (re: Ki = 17nM), thus potentially including both CNS and peripheral influences on the observed weight loss. Overall, these studies suggest that marked improvements in aspects of metabolic disease and alcoholic steatosis can be realized with CB1R neutral antagonists and hence warrants the exploration of further members of this class of cannabinoid ligands.

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“…A set of CB1 antagonists containing the pyrazine scaffold such as 5,6-diaryl-pyrazine-2-amide 36 and its corresponding thioamide 37, readily prepared by treatment of 36 with Lawesson's reagent [50], has been reported by Boström and co-workers for weight reduction [51]. Interestingly, the authors report that the thioamides not only displayed retained potency towards CB1R (below 10 nM), but also showed improved solubility versus the carboxamides, which is contradictory to the general trend for these "matched-pairs" [52].…”

Section: Miscellaneous Chemical Entities Acting As Peripheral Cb1r Anmentioning

confidence: 98%

A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

Wu¹,

Yeh²,

Ly³

et al. 2011

CTMC

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Since Rimonabant was withdrawn in Europe in 2008 because of its substantial CNS risk factors including depression and anxiety, the development of anti-obesity drugs targeting CB1R in the brain has been suspended and/or terminated globally. Instead, developing peripherally restricted CB1R antagonists is actively pursued in the hope that not only could they eliminate any CNS adverse effects observed with Rimonabant, but also maintain therapeutic benefits in metabolic syndrome, including obesity, type 2 diabetes, and non-alcoholic fatty liver diseases. In this review, we summarized the most recent advances that have been made on this area, with particular emphasis on various synthetic approaches, whereby the increase in polarity, water solubility and polar surface area were centralized on, toward potential peripheral-acting CB1 antagonists.

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Novel thioamide derivatives as neutral CB1 receptor antagonists

Cited by 25 publications

References 16 publications

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Rimonabant Redux and Strategies to Improve the Future Outlook of CB1 Receptor Neutral‐Antagonist/Inverse‐Agonist Therapies

Metabolic Profiling of CB1 Neutral Antagonists

A New Perspective of Cannabinoid 1 Receptor Antagonists: Approaches Toward Peripheral CB1R Blockers without Crossing the Blood-Brain Barrier

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