A5089764806- Cannabis and Cannabinoid Research
- Peroxisome Proliferator-Activated Receptors
- Herpesvirus Infections and Treatments
- Sphingolipid Metabolism and Signaling
- Cytomegalovirus and herpesvirus research
- Pharmacological Receptor Mechanisms and Effects
- Toxin Mechanisms and Immunotoxins
- Drug-Induced Hepatotoxicity and Protection
- Pharmacogenetics and Drug Metabolism
- Lysosomal Storage Disorders Research
- Synthesis and Biological Evaluation
- Diabetes Treatment and Management
- Parkinson's Disease Mechanisms and Treatments
- Plant Gene Expression Analysis
- Synthesis and biological activity
- Polyamine Metabolism and Applications
- Wound Healing and Treatments
- Adenosine and Purinergic Signaling
- Microbial Metabolism and Applications
- Alcohol Consumption and Health Effects
- Amyotrophic Lateral Sclerosis Research
- Cardiac Structural Anomalies and Repair
- Calcium signaling and nucleotide metabolism
- Phytochemistry and biological activities of Ficus species
- Neuroinflammation and Neurodegeneration Mechanisms
Aptuit (Italy)
2020-2023
Italian Institute of Technology
2012-2020
University of Leeds
2009-2015
Cardiff University
2007-2008
Rega Institute for Medical Research
2007
KU Leuven
2007
Pain and inflammation are major therapeutic areas for drug discovery. Current drugs these pathologies have limited efficacy, however, often cause a number of unwanted side effects. In the present study, we identify nonsteroidal anti-inflammatory carprofen as multitarget-directed ligand that simultaneously inhibits cyclooxygenase-1 (COX-1), COX-2, fatty acid amide hydrolase (FAAH). Additionally, synthesized tested several derivatives carprofen, sharing this multitarget activity. This may...
The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy these drugs, as well their propensity damage gastrointestinal (GI) epithelium. This toxic action greatly limits use NSAIDs in inflammatory bowel disease (IBD) other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades endocannabinoid anandamide, which attenuates inflammation promotes GI healing. Here, we describe first class systemically...
Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase risk for developing Parkinson's disease a dominantly inherited fashion. These pathogenic variants, of which G2019S is most common, cause abnormally high activity, and compounds inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, inhibitors can selectively target variant while sparing normal could offer...
To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to point of Phase 1 clinical trial for herpes zoster.A new chromatography-free synthetic access lead anti-VZV BCNAs is reported. The activity Cf1743 was evaluated in monolayer cell cultures and organotypic epithelial raft primary human keratinocytes. Oral dosing rodents preliminary pharmacokinetics assessment made, followed by an exploration alternative formulations preparation pro-drugs. We also...
Background and Purpose The TRPC5 proteins assemble to create calcium‐permeable, non‐selective, cationic channels. We sought novel modulators of these channels through studies natural products. Experimental Approach Intracellular calcium measurements patch clamp recordings were made from cell lines. Compounds generated by synthetic chemistry. Key Results Through a screen products used in traditional Chinese medicines, the flavonol galangin was identified as an inhibitor lanthanide‐evoked...
Abstract Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions terminated by the intracellular cysteine amidase, N ‐acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti‐inflammatory therapy, lipid‐like structures reactive warheads of current inhibitors limit use these agents as oral drugs. A series novel benzothiazole–piperazine derivatives inhibit in potent selective manner...
Significance Healthy human skin quickly repairs itself when wounded. Skin healing is essential for survival, and it depends on a well-ordered sequence of molecular cellular events that require the cooperation several growth-promoting proteins released by cells or produced in extracellular matrix. In present study, we identify family lipid-derived molecules accelerate closure self-repairing wounds. These endogenous substances promote migration epidermal keratinocytes differentiation dermal...
Acid ceramidase (AC) is a cysteine hydrolase that plays crucial role in the metabolism of lysosomal ceramides, important members sphingolipid family, diversified class bioactive molecules mediate many biological processes ranging from cell structural integrity, signaling, and proliferation to death. In effort expand diversity existing collection AC inhibitors, novel substituted oxazol-2-one-3-carboxamides were designed synthesized. Herein, we present chemical optimization our initial hits,...
Alzheimer's disease (AD) is a slow-progressing of the brain characterized by symptoms such as impairment memory and other cognitive functions. AD associated with an inflammatory process that involves astrocytes microglial cells, among components. Astrocytes are most abundant type glial cells in central nervous system (CNS). They involved inducing neuroinflammation. The present study uses astrocyte-neuron cocultures to investigate how ARN14494, serine palmitoyltransferase (SPT) inhibitor,...
Sphingolipids (SphLs) are a diverse class of molecules that regulated by complex network enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation several SphL-related disorders. Acid ceramidase is one the key enzymes regulate metabolism ceramides glycosphingolipids, which important members SphL family. Herein, we describe lead optimization studies benzoxazolone carboxamides resulting piperidine 22m, where demonstrated target engagement two animal models...
Carbocyclic nucleoside analogues are catabolically stable since they resistant to phosphorolytic cleavage by pyrimidine phosphorylase enzymes. The carbocyclic analogue (C-BCNA) of the highly potent and selective anti-VZV bicyclic (BCNA) 6-pentylphenylfuro[2,3-d]pyrimidine-2′-deoxyribose was synthesized using 2′-deoxyuridine as starting material. C-BCNA found be chemically more than furano lead, but it shown significantly less antivirally active its parent analogue. It noted have a 10-fold...
Abstract Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions terminated by the intracellular cysteine amidase, N ‐acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti‐inflammatory therapy, lipid‐like structures reactive warheads of current inhibitors limit use these agents as oral drugs. A series novel benzothiazole–piperazine derivatives inhibit in potent selective manner...
Abstract Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of valosin-containing protein (VCP)-associated inclusion body myopathy associated with Paget disease bone, frontotemporal dementia and amyotrophic lateral sclerosis. Ceramide (d18:1/16:0) levels elevated in skeletal muscle the mice, compared to wild-type controls. Moreover, exposure lipid-enriched diet reverses lethality, improves normalizes ceramide these suggesting that dysfunctions lipid-derived signaling critical...
The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H<sub>2</sub> (PGH<sub>2</sub>). also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) arachidonoylethanolamide (AEA) corresponding PGH<sub>2</sub> analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy counter this toxicity inhibit fatty amide hydrolase (FAAH),...
Activity-based protein profiling (ABPP) is a method for the identification of an enzyme interest in complex proteome through use chemical probe that targets enzyme's active sites. A reporter tag introduced into allows detection labeled by in-gel fluorescence scanning, blot, microscopy, or liquid chromatography-mass spectrometry. Here, we describe preparation and compound ARN14686, click chemistry activity-based (CC-ABP) selectively recognizes N-acylethanolamine acid amidase (NAAA). NAAA...
Activity-based protein profiling (ABPP) is a method for the identification of an enzyme interest in complex proteome through use chemical probe that targets enzyme's active sites. A reporter tag introduced into allows detection labeled by in-gel fluorescence scanning, blot, microscopy, or liquid chromatography-mass spectrometry. Here, we describe preparation and compound ARN14686, click chemistry activity-based (CC-ABP) selectively recognizes N-acylethanolamine acid amidase (NAAA). NAAA...