Identification of a novel arylpiperazine scaffold for fatty acid amide hydrolase inhibition with improved drug disposition properties

Butini, Stefania; Gemma, Sandra; Brindisi, Margherita; Maramai, Samuele; Minetti, Patrizia; Celona, Diana; Napolitano, Roberto; Borsini, Franco; Cabri, Walter; Fezza, Filomena; Merlini, Lucio; Dallavalle, Sabrina; Campiani, Giuseppe; Maccarrone, Mauro

doi:10.1016/j.bmcl.2012.11.035

Cited by 15 publications

(16 citation statements)

References 22 publications

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“…Moreover, in vivo studies evidenced its robust analgesic activity in mouse models of thermal hyperalgesia and neuropathic pain [129] . Recently, Brindisi and co‐workers disclosed novel FAAH inhibitors [130,131,132,133] . Among them, tricyclic compound 22 (IC 50 =83.5 nM on r FAAH, Figure 5) behaved as potent and selective FAAH inhibitor.…”

Section: Faah Inhibitors In Msmentioning

confidence: 99%

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

Maramai

Brindisi

2020

ChemMedChem

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Multiple sclerosis (MS) is a chronic, immune‐mediated disease of the central nervous system. At present, there is no definitive cure, and the few available disease‐modifying options display either poor efficacy or life‐threatening side effects. There is clear evidence that relapsing‐remitting clinical attacks in MS are driven by inflammatory demyelination and that the subsequent disease steps, being irresponsive to immunotherapy, result from neurodegeneration. The endocannabinoid system (ECS) stands halfway between three key pathomechanisms underlying MS, namely inflammation, neurodegeneration and oxidative stress, thus representing a kingpin for the identification of novel therapeutic targets in MS. This review summarizes the current state of the art in the field of endocannabinoid metabolism modulators and their in vivo effects on relevant animal models. We also highlight key molecular underpinnings of their therapeutic efficacy as well as the potential to turn them into promising clinical candidates.

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Section: Faah Inhibitors In Msmentioning

confidence: 99%

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

Maramai

Brindisi

2020

ChemMedChem

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“…These findings suggested that the modulation of ECS may have a profound impact on AD. ECS can be modulated either by direct stimulation of CBRs or by inhibition of the ECB catabolic enzymes, leading to increased levels of ECBs [100][101][102][103][104]. For this latter purpose, Montanari et al have recently proposed some compounds, here represented by 39 (Figure 13), endowed with inhibitory 13 BioMed Research International activity towards FAAH, AChE, and BuChE [105].…”

Section: The Effects Of Dual Che Inhibitors and Modulators Of Thementioning

confidence: 99%

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

Maramai

Benchekroun

Gabr

et al. 2020

BioMed Research International

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Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.

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“…Of these, roles in fatty acid amide inactivation [31]. Hence, FAAHI blockers are also developed as one of the efficient cancer therapies so that CB1 signal transduction may happen uninterrupted to kill cancerous cells [19,32,33]. In addition, we also reviewed all plausible signal transduction pathways that could relate CB1 stimulation to cancer cell death.…”

Section: Introductionmentioning

confidence: 99%

3-Hydroxypropane-1,2-Diyl Dipalmitoleate—A Natural Compound with Dual Roles (CB1 Agonist/FAAH1 Blocker) in Inhibiting Ovarian Cancer Cell Line

Sathynathan

Raman

Sivamurugan³

et al. 2021

Pharmaceuticals

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Though it was once known that upregulated Cannabinoid Receptor (CB1) and downregulated Fatty Acid Amide Hydrolase (FAAH1) are associated with tumour aggressiveness and metastasis, it is now clear that upregulated CB1 levels more than a certain point cause accumulation of ceramide and directs cells to apoptosis. Hence, CB1 analogues/FAAH1 blockers are explored widely as anticancer drugs. There are reports on CB1-agonists and FAAH1-blockers separately, however, dual activities along with ovarian cancer-specific links are not established for any natural compound. With this setting, we describe for the first time the isolation of 3-hydroxypropane-1,2-diyl dipalmitoleate (564.48 Da) from a marine snail, Conus inscriptus, which binds to both CB1 and FAAH1 (glide energies: −70.61 and −30.52 kcal/mol, respectively). MD simulations indicate stable compound–target interaction for a minimum of 50 nanoseconds with relative invariabilities in Rg. The compound inhibited ovarian cancer cell line, PA1 at 1.7 μM. Structural and chemical interpretation of the compound (C2) was done using FT-IR, GC-MS, ESI-MS, 1H and 13C-NMR (1 and 2D). Furthermore, a probable route for gram-scale synthesis of C2 is hinted herein. With the available preliminary data, molecular mechanisms involving dual roles for this potent molecule must be elucidated to understand the possibilities of usage as an anticancer drug.

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Identification of a novel arylpiperazine scaffold for fatty acid amide hydrolase inhibition with improved drug disposition properties

Cited by 15 publications

References 22 publications

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

Multitarget Therapeutic Strategies for Alzheimer’s Disease: Review on Emerging Target Combinations

3-Hydroxypropane-1,2-Diyl Dipalmitoleate—A Natural Compound with Dual Roles (CB1 Agonist/FAAH1 Blocker) in Inhibiting Ovarian Cancer Cell Line

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