Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters

Zindell, Renée; Walker, Edward R.; Scott, John; Amouzegh, Patricia; Wu, Lijie; Ermann, Monika; Thomson, D. S.; Fisher, Micheal B.; Fullenwider, Cody L.; Grbic, Heather; Kaplita, Paul V.; Linehan, Brian; Patel, Mita; Patel, Monica; Löbbe, Sabine; Block, Svenja; Albrecht, Claudia; Gemkow, Mark J.; Shih, Daw-Tsun; Riether, Doris

doi:10.1016/j.bmcl.2011.05.068

Cited by 11 publications

(6 citation statements)

References 17 publications

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“…Several other five-membered heterocycles comprising a tert -butyl group have also appeared (e.g., 115 – 117 , − 119 – 122 − ). Pyrazolylamide 115 is representative of a CB 2 agonist chemotype reported by Amgen.…”

Section: Medicinal Chemistrymentioning

confidence: 99%

“…Several recent publications describe the causal relationship between the diazepamylamide and pharmaceutical properties. , One study focused on improving metabolic stability and pharmacokinetics by targeting analogues with reduced relative lipophilicity. Tetrahydropyran 121 (Figure ) was the best molecule in this respect, having improved stability (HLM t 1/2 > 120 min), a clean CYP profile (2D6, 2C9, 3A4, >30 μM), and improved rat pharmacokinetics ( F = 28%, AUC 0–inf = 1.38 μmol h –1 L –1 , C max = 1.76 μg/mL, 10 μmol/kg, po).…”

Section: Medicinal Chemistrymentioning

confidence: 99%

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Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

et al. 2013

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The cannabinoid receptor type 2 (CB2) is a class A GPCR that was cloned in 1993 while looking for an alternative receptor that could explain the pharmacological properties of Δ(9)-tetrahydrocannabinol. CB2 was identified among cDNAs based on its similarity in amino acid sequence to the CB1 receptor and helped provide an explanation for the established effects of cannabinoids on the immune system. In addition to the immune system, CB2 has widespread tissue expression and has been found in brain, peripheral nervous system, and gastrointestinal tract. Several "mixed" cannabinoid agonists are currently in clinical use primarily for controlling pain, and it is believed that selective CB2 agonism may afford a superior analgesic agent devoid of the centrally mediated CB1 effects. Thus, selective CB2 receptor agonists represent high value putative therapeutics for treating pain and other disease states. In this Perspective, we seek to provide a concise update of progress in the field.

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Section: Medicinal Chemistrymentioning

confidence: 99%

Section: Medicinal Chemistrymentioning

confidence: 99%

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

et al. 2013

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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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“…The pharmacokinetic profile of compound 80 (EC 50 = 67 nM) bearing an isoxazole (Figure ), a more polar substituent, in concomitance with the tetrahydropyran fragment in various in vitro assays was more favorable than that of the phenyl urea 79 . Expanding upon the tetrahydropyran substituent, analog 81 (Figure ) was synthesized and greatly enhanced CB 2 potency (EC 50 = 1 nM) and selectivity and improved the aqueous solubility …”

Section: Chemistry Of Cb2 Agonistsmentioning

confidence: 99%

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB₂ Receptor Agonists

et al. 2016

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mino)-4-cyclopropyl-N-(tetrahydro-2Hpyran-4-yl)methyl)pyridine-3-carboxamide (2) 532 7.1.2. Preparation of 4-(6-((2R,5S)-2,5-Dimethylpyrrolidin-1-yl)pyridazin-3-yl)isoquinoline (6) 532 7.2. Sulfamoyl Benzamide 532 7.2.1. Preparation of N-[3,4-Dimethyl-5-(morpholin-4-ylsulfonyl)phenyl]-2,2-dimethyl butanamide (15) 532 7.3. Heterocyclic Ylidene 532 7.3.1. Preparation of (14E)-N-(3-tert-butyl-1-(Cyclopropylmethyl)-1,2-dihydro-2methylpyrazol-5-ylidene)-2-fluoro-3-(trifluoromethyl)benzamide (22) 533 7.4. Oxadiazole, α-Amidosulfone 533

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Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters

Cited by 11 publications

References 17 publications

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

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

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB₂ Receptor Agonists

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Aryl 1,4-diazepane compounds as potent and selective CB2 agonists: Optimization of drug-like properties and target independent parameters

Cited by 11 publications

References 17 publications

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB2) Selective Agonists

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB2) Selective Agonists

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

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB2 Receptor Agonists

Contact Info

Product

Resources

About

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

Therapeutic Utility of Cannabinoid Receptor Type 2 (CB₂) Selective Agonists

Medicinal Chemistry, Pharmacology, and Potential Therapeutic Benefits of Cannabinoid CB₂ Receptor Agonists