1,4-Diazepane compounds as potent and selective CB2 agonists: Optimization of metabolic stability

Riether, Doris; Wu, Lijie; Cirillo, Pier F.; Berry, Angela; Walker, Edward R.; Ermann, Monika; Noya-Marino, Beatriz; Jenkins, James E.; Albaugh, Dan; Albrecht, Claudia; Fisher, Michael T.; Gemkow, Mark J.; Grbic, Heather; Löbbe, Sabine; Möller, Clemens; O’Shea, Kathy; Sauer, Achim; Shih, Daw-Tsun; Thomson, D. S.

doi:10.1016/j.bmcl.2011.02.017

Cited by 19 publications

(16 citation statements)

References 18 publications

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“…Since its first application to measuring the hERG channel for safety screening (Kiss et al, 2003), this technique has been well validated for a number of robots. It is now widely applied to reduce the liability of compound series’ towards the hERG channel as part of safety pharmacology assessment early during medicinal chemistry compound development (Kutchinsky et al, 2003; Davenport et al, 2010; Riether et al, 2011; Tye et al, 2011). Reported correlations of biophysical channel properties (Figure 2) as well as pharmacological compound properties between automated (planar, chip-based) and manual (pipette-based) patch-clamp investigations are generally excellent (Kutchinsky et al, 2003; Xu et al, 2003; Tao et al, 2004; Bridgland-Taylor et al, 2006; Jones et al, 2009; Davenport et al, 2010; Golden et al, 2011).…”

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

“…Never before has it been practically possible for pharmaceutical companies to screen compounds on the order of tens of thousands against an ion channel target by use of a direct functional readout, and thus avoiding the potential false positives and/or negatives associated to other, more indirect (such as fluorescence assay or binding techniques), high-throughput screening methods. This has allowed drug developers to move cardiac ion channel safety screening earlier into the drug development pipeline, and to mitigate potential cardiac safety liabilities of potent compound series (Davenport et al, 2010; Riether et al, 2011; Tye et al, 2011). …”

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

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Automated electrophysiology makes the pace for cardiac ion channel safety screening

Möller

Witchel

2011

Front. Pharmacol.

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The field of automated patch-clamp electrophysiology has emerged from the tension between the pharmaceutical industry’s need for high-throughput compound screening versus its need to be conservative due to regulatory requirements. On the one hand, hERG channel screening was increasingly requested for new chemical entities, as the correlation between blockade of the ion channel coded by hERG and torsades de pointes cardiac arrhythmia gained increasing attention. On the other hand, manual patch-clamping, typically quoted as the “gold-standard” for understanding ion channel function and modulation, was far too slow (and, consequently, too expensive) for keeping pace with the numbers of compounds submitted for hERG channel investigations from pharmaceutical R&D departments. In consequence it became more common for some pharmaceutical companies to outsource safety pharmacological investigations, with a focus on hERG channel interactions. This outsourcing has allowed those pharmaceutical companies to build up operational flexibility and greater independence from internal resources, and allowed them to obtain access to the latest technological developments that emerged in automated patch-clamp electrophysiology – much of which arose in specialized biotech companies. Assays for nearly all major cardiac ion channels are now available by automated patch-clamping using heterologous expression systems, and recently, automated action potential recordings from stem-cell derived cardiomyocytes have been demonstrated. Today, most of the large pharmaceutical companies have acquired automated electrophysiology robots and have established various automated cardiac ion channel safety screening assays on these, in addition to outsourcing parts of their needs for safety screening.

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Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Möller

Witchel

2011

Front. Pharmacol.

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“…In addition to providing insight into the components of the pathophysiology of allergic asthma, our study suggests that the ECS could be explored as a potential therapeutic target. Currently, academic researchers and pharmaceutical companies are pursuing the development of selective CB2 agonists for the treatment of pain and inflammation 23 , 24 , 25 , 26 . Given the abundant CB2 expression in eosinophils, CB2 modulation via selective CB2 agonists could be a novel strategy for the treatment of inflammatory airway diseases, including allergic asthma.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, academic researchers and pharmaceutical companies are pursuing the development of selective CB2 agonists for the treatment of pain and inflammation. [23][24][25][26] Given the abundant CB2 expression in eosinophils, CB2 modulation via selective CB2 agonists could be a novel strategy for the treatment of inflammatory airway diseases, including allergic asthma. Pharmacological FAAH inhibition is a reasonable alternative strategy.…”

Section: Discussionmentioning

confidence: 99%

Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma

Zoerner

Stichtenoth

Engeli

et al. 2011

Clin Pharmacol Ther

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Preclinical studies suggest that the endocannabinoid anandamide restrains allergic airway obstruction and inflammation. Therefore, we applied saline or allergens via bronchoscopy into different lung segments of patients with allergic asthma. Twenty‐four hours later, anandamide concentrations in bronchoalveolar lavage fluids had increased more than fourfold. Anandamide concentrations correlated with severity of airway inflammation. These observations suggest that allergen exposure specifically activates the pulmonary endocannabinoid system (ECS) in patients with allergic asthma. Clinical Pharmacology & Therapeutics (2011) 90 3, 388–391. doi:

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“…Lastly, other different structures with high selectivity to CB2 receptors, such as sulphone [177], arylsulphonamide, [178] amidosulphone [179], 1,4-Diazepane and proline [180,181] derivatives should be mentioned, which behave as cannabinoid receptor agonists (Fig. 14).…”

Section: Other Synthetic Cannabinoid Structuresmentioning

confidence: 99%

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

Páez

Campillo

2019

CMC

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The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer's disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.

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1,4-Diazepane compounds as potent and selective CB2 agonists: Optimization of metabolic stability

Cited by 19 publications

References 18 publications

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Allergen Challenge Increases Anandamide in Bronchoalveolar Fluid of Patients With Allergic Asthma

Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s Disease and Less Well-Known Diseases

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