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3 results on '"Pontis S"'

1. Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.

Author

Migliore M Dr, Pontis S Dr, Fuentes de Arriba AL, Realini N, Torrente E, Armirotti A, Romeo E, Di Martino S, Russo D, Pizzirani D, Summa M, Lanfranco M, Ottonello G, Busquet P, Jung KM, Garcia-Guzman M, Heim R, Scarpelli R, and Piomelli D

Subjects
Administration, Oral, Amides, Amidohydrolases metabolism, Animals, Dose-Response Relationship, Drug, Endocannabinoids administration & dosage, Endocannabinoids chemistry, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Ethanolamines administration & dosage, Ethanolamines chemistry, Mice, Molecular Structure, Multiple Sclerosis metabolism, Oleic Acids administration & dosage, Oleic Acids chemistry, Palmitic Acids administration & dosage, Palmitic Acids chemistry, Structure-Activity Relationship, Amidohydrolases antagonists & inhibitors, Disease Models, Animal, Endocannabinoids pharmacology, Enzyme Inhibitors pharmacology, Ethanolamines pharmacology, Multiple Sclerosis drug therapy, Oleic Acids pharmacology, Palmitic Acids pharmacology
Abstract

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2016
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2. An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freund's Adjuvant Rat Model of Arthritis.

Author

Bonezzi, FT, Sasso, O, Pontis, S, Realini, N, Romeo, E, Ponzano, S, Nuzzi, A, Fiasella, A, Bertozzi, F, and Piomelli, D

Subjects
Animals, Rats, Rats, Sprague-Dawley, Arthritis, Experimental, Amidohydrolases, Freund's Adjuvant, Enzyme Inhibitors, Male, Pharmacology & Pharmacy, Pharmacology and Pharmaceutical Sciences
Abstract

The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-α. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFA-induced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis.

Published
2016

3. Acid Ceramidase in Melanoma: EXPRESSION, LOCALIZATION, AND EFFECTS OF PHARMACOLOGICAL INHIBITION*

Author

Realini, N, Palese, F, Pizzirani, D, Pontis, S, Basit, A, Bach, A, Ganesan, A, and Piomelli, D

Subjects
Keratinocytes, Skin Neoplasms, Acid Ceramidase, Cell Survival, Serine C-Palmitoyltransferase, Down-Regulation, Ceramides, Inhibitory Concentration 50, Sphingosine, Cell Line, Tumor, Humans, Enzyme Inhibitors, RNA, Small Interfering, Uracil, Melanoma, Cell Proliferation, Sphingolipids, Microscopy, Confocal, Hep G2 Cells, Fibroblasts, HCT116 Cells, Lipids, Gene Expression Regulation, Neoplastic, Microscopy, Fluorescence, MCF-7 Cells, Melanocytes, Lysophospholipids, Oxidoreductases, Signal Transduction
Abstract

Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingolipid signaling in melanoma. We found that AC expression is markedly elevated in normal human melanocytes and proliferative melanoma cell lines, compared with other skin cells (keratinocytes and fibroblasts) and non-melanoma cancer cells. High AC expression was also observed in biopsies from human subjects with Stage II melanoma. Immunofluorescence studies revealed that the subcellular localization of AC differs between melanocytes (where it is found in both cytosol and nucleus) and melanoma cells (where it is primarily localized to cytosol). In addition to having high AC levels, melanoma cells generate lower amounts of ceramides than normal melanocytes do. This down-regulation in ceramide production appears to result from suppression of the de novo biosynthesis pathway. To test whether AC might contribute to melanoma cell proliferation, we blocked AC activity using a new potent (IC50 = 12 nM) and stable inhibitor. AC inhibition increased cellular ceramide levels, decreased sphingosine 1-phosphate levels, and acted synergistically with several, albeit not all, antitumoral agents. The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation.

Published
2015
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