Synthesis, Molecular Pharmacology, and Structure–Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists

Fulo, Harvey F.; Shoeib, Amal; Cabanlong, Christian V.; Williams, Alexander H.; Zhan, Chang‐Guo; Prather, Paul L.; Dudley, Gregory B.

doi:10.1021/acs.jmedchem.1c00442

Cited by 14 publications

(7 citation statements)

References 72 publications

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“…For example, a selective CB 2 R ligand 49 showed a selectivity index equal to 30.5. 44 As reported in Figure 8a, the pentynyl chain along with the benzoyl groups are fundamental for the correct prediction.…”

Section: ■ Results and Discussionmentioning

confidence: 90%

CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning

Gambacorta,

Ciriaco,

Amoroso

et al. 2023

J. Chem. Inf. Model.

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The endocannabinoid system, which includes cannabinoid receptor 1 and 2 subtypes (CB 1 R and CB 2 R, respectively), is responsible for the onset of various pathologies including neurodegeneration, cancer, neuropathic and inflammatory pain, obesity, and inflammatory bowel disease. Given the high similarity of CB 1 R and CB 2 R, generating subtype-selective ligands is still an open challenge. In this work, the Cannabinoid Iterative Revaluation for Classification and Explanation (CIRCE) compound prediction platform has been generated based on explainable machine learning to support the design of selective CB 1 R and CB 2 R ligands. Multilayer classifiers were combined with Shapley value analysis to facilitate explainable predictions. In test calculations, CIRCE predictions reached ∼80% accuracy and structural features determining ligand predictions were rationalized. CIRCE was designed as a web-based prediction platform that is made freely available as a part of our study.

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Section: ■ Results and Discussionmentioning

confidence: 90%

CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning

Gambacorta,

Ciriaco,

Amoroso

et al. 2023

J. Chem. Inf. Model.

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“…Our general approach to this challenge has been to develop ring-opening fragmentation reactions , that can leverage dimedone (Figure ) to give rise to bifunctional neopentylene-tethered building blocks for chemical synthesis (e.g., tethered alkynyl ketones, , 1,6-enynes, ,, etc.). For example, benzannulation of neopentylene-tethered π-systems can produce dimethylindanes; we reported an oxidative cycloisomerization of dienyne 3 that provides benzoate 4 in 4 steps (∼56% overall) from dimedone (Scheme ), and we produced 4 on a gram scale in connection with other on-going projects in our lab . Here we report an improved synthesis of neoprofen by this general approach, augmented with critical methodological examination and key innovations in metal-catalyzed benzannulation and hydrocarboxylation reactions (Figure ).…”

Section: Results and Discussionmentioning

confidence: 99%

Benzannulation and Hydrocarboxylation Methods for the Synthesis of a Neopentylene-Fused Analogue of Ibuprofen

et al. 2021

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Neopentylene ring fusions (ring-fused 4,4-dimethylcyclopentane polycycles) are found in many natural products, but they are largely absent from synthetic compound libraries and focused medicinal chemistry research. Here is reported a synthetic approach to one of the few non-natural product-based target compounds from medicinal chemistry that includes a neopentylene ring fusion: an analogue of ibuprofen referred to herein as “neoprofen”. The approach features ring-opening fragmentation reactions of dimedone derivatives coupled with transition metal-catalyzed benzannulation and hydrocarboxylation methods.

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“…These aminomethylindole compounds offered a new outlook for the development drugs for neurodegenerative disorders. Dudley and co-workers [112] developed a new class of indole cannabinoids (73) for human CB2 receptors. These compounds showed high affinity and a good selectivity index towards receptors.…”

Section: Alzheimer's Disease Activitymentioning

confidence: 99%

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

Mathada¹,

Yernale

Basha³

2023

ChemistrySelect

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Heterocycles are a privileged motif that appears as a momentous objective in medicinal chemistry. An important class of compounds for drug discovery and design is indole and its derivatives, which have been examined for a variety of biological activities. Therefore, it is noteworthy in the modern progress of synthetic, medicinal chemistry; the last decade has been onlooker with a multitude of reports on several indole derivatives corroborating these chemical entities to be a renowned target for the discovery of new drugs. The current study includes brief natural sources of indole, and a new range of commercially available indole‐based drugs. Additionally, this review discusses the numerous facets of the structure‐activity relationship study (SARs) and provides information about the varied pharmacological effects of indole derivatives. The literature data presented for the anti‐pharmacological agents herein covers largely from the year 2015 to mid of 2022.

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Synthesis, Molecular Pharmacology, and Structure–Activity Relationships of 3-(Indanoyl)indoles as Selective Cannabinoid Type 2 Receptor Antagonists

Cited by 14 publications

References 72 publications

CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning

CIRCE: Web-Based Platform for the Prediction of Cannabinoid Receptor Ligands Using Explainable Machine Learning

Benzannulation and Hydrocarboxylation Methods for the Synthesis of a Neopentylene-Fused Analogue of Ibuprofen

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

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