ARN19702
目录号 : GC63794ARN19702 is an orally active, reversible N-Acylethanolamine acid amidase(NAAA) inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice.
Cas No.:1971937-18-4
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ARN19702 is an orally active, reversible N-Acylethanolamine acid amidase(NAAA) inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice.
ARN19702 is a selective, orally active, reversible and brain-penetrant N-acylethanolamine acid amidase (NAAA), by a non-covalent mechanism.[1]
ARN-19702 attenuates the spontaneous nocifensive response elicited and the hypersensitivity in male mouse model of acute and neuropathic pain, also reduces nociception associated with paclitaxel-induced neuropathy without development of subacute antinociceptive tolerance in male rat model of acute and neuropathic pain.[2]
[1] Migliore M Dr, et al. Angew Chem Int Ed Engl. 2016 Sep 5;55(37):11193-11197. [2] Fotio Y, et al. J Pharmacol Exp Ther. 2021 Aug;378(2):70-76.
Cas No. | 1971937-18-4 | SDF | Download SDF |
分子式 | C21H22FN3O3S2 | 分子量 | 447.55 |
溶解度 | 储存条件 | Store at -20°C | |
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Antinociceptive Profile of ARN19702, (2-Ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone, a Novel Orally Active N-Acylethanolamine Acid Amidase Inhibitor, in Animal Models
J Pharmacol Exp Ther 2021 Aug;378(2):70-76.PMID:33986036DOI:10.1124/jpet.121.000674.
N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiologic actions of palmitoylethanolamide, an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-α We have previously reported that the compound ARN19702 [(2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone] is an orally active, reversible NAAA inhibitor (IC50 on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hypersensitivity caused by intraplantar carrageenan injection, paw incision, or sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of subacute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. SIGNIFICANCE STATEMENT: This study evaluated the pharmacological profile of the orally bioavailable N-acylethanolamine acid amidase (NAAA) inhibitor (2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone (ARN19702) in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. It is concluded that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. The findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential .
Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition
Exp Neurol 2022 Nov;357:114194.PMID:35932800DOI:10.1016/j.expneurol.2022.114194.
The intracellular lipid amidases, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA), terminate the actions of anandamide and palmitoylethanolamide (PEA), two antinociceptive and anti-inflammatory lipid-derived mediators. Here we show, confirming prior research, that small-molecule inhibitors of peripheral FAAH (compound URB937) and systemic NAAA (compound ARN19702) individually attenuate, in male CD-1 mice, pain-related behaviors and paw inflammation in the formalin and carrageenan tests. More importantly, isobolographic analyses revealed that the combination of URB937 and ARN19702 produced substantial synergistic (greater than additive) antinociceptive effects in both models as well as additive anti-inflammatory effects in the carrageenan test. Together, the findings uncover a functional interplay between FAAH and NAAA substrates in the control of nociception, which might be exploited clinically to develop safe and effective pain management strategies.
N-acylethanolamine acid amidase (NAAA) inhibition decreases the motivation for alcohol in Marchigian Sardinian alcohol-preferring rats
Psychopharmacology (Berl) 2021 Jan;238(1):249-258.PMID:33037452DOI:10.1007/s00213-020-05678-7.
Rationale: N-acylethanolamine acid amidase (NAAA) is an intracellular cysteine hydrolase that terminates the biological actions of oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), two endogenous lipid-derived agonists of the nuclear receptor, and peroxisome proliferator-activated receptor-α. OEA and PEA are important regulators of energy balance, pain, and inflammation, but recent evidence suggests that they might also contribute to the control of reward-related behaviors. Objectives and methods: In the present study, we investigated the effects of systemic and intracerebral NAAA inhibition in the two-bottle choice model of voluntary alcohol drinking and on operant alcohol self-administration. Results: Intraperitoneal injections of the systemically active NAAA inhibitor ARN19702 (3 and 10 mg/kg) lowered voluntary alcohol intake in a dose-dependent manner, achieving ≈ 47% reduction at the 10 mg/kg dose (p < 0.001). Water, food, or saccharin consumption was not affected by the inhibitor. Similarly, ARN19702 dose-dependently attenuated alcohol self-administration under both fixed ratio 1 (FR-1) and progressive ratio schedules of reinforcement. Furthermore, microinjection of ARN19702 (1, 3 and 10 μg/μl) or of two chemically different NAAA inhibitors, ARN077 and ARN726 (both at 3 and 10 μg/μl), into the midbrain ventral tegmental area produced dose-dependent decreases in alcohol self-administration under FR-1 schedule. Microinjection of ARN19702 into the nucleus accumbens had no such effect. Conclusion: Collectively, the results point to NAAA as a possible molecular target for the treatment of alcohol use disorder.