- Synthesis of Acetaminophen Analogues Containing α-Amino Acids and Fatty Acids for Inhibiting Hepatotoxicity
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Acetaminophen is a popular antipyretic analgesic medicine that has weaker anti-inflammatory properties and lower incidence of side effects than nonsteroidal anti-inflammatory drugs (NSAIDs). However, acetaminophen causes hepatotoxicity due to the reactive metabolite N -acetyl- p -benzoquinone imine (NAPQI). We have obtained acetaminophen analogues in 57-99percent yields by using aniline derivatives with protected α-amino acids and fatty acids via the corresponding mixed carbonic carboxylic anhydrides in aqueous MeCN. We have also succeeded in synthesizing AM404 analogues in 76-97percent yields, which are expected to be promising candidates for reducing hepatotoxicity.
- Imai, Nobuyuki,Jung, Seunghee,Kawashima, Yuya,Noguchi, Takuya
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p. 3686 - 3696
(2019/09/30)
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- A Convenient Protocol for the Synthesis of Fatty Acid Amides
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Several classes of biologically occurring fatty acid amides have been reported from mammalian and plant sources. Many amides conjugated with fatty acids of mammalian origin exhibit specific activation of individual receptors. Their potential as pharmacological tools or as lead compounds towards the development of novel therapeutics is of great interest. Hence, access to such amides by a practical, high-yielding and scalable protocol without affecting the geometry or position of sensitive functionalities is needed. A protocol that meets all these requirements involves activation of the corresponding acid with carbonyl diimidazole (CDI) followed by reaction with the desired amine or its hydrochloride. More than fifty compounds have been prepared in generally high yields.
- Johansson, Silje J. R.,Johannessen, Tonje,Ellefsen, Christiane F.,Ristun, Mali S.,Antonsen, Simen,Hansen, Trond V.,Stenstrom, Yngve,Nolsoe, Jens M. J.
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supporting information
p. 213 - 217
(2019/01/14)
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- New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide
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N-(4-Hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide (AM404) is a metabolite of the well-known analgesic paracetamol. AM404 inhibits endocannabinoid cellular uptake, binds weakly to CB1 and CB 2 cannabinoid receptors, and is formed by fatty acid amide hydrolase (FAAH) in vivo. We prepared three derivatives of this new (endo)cannabinoid using bioisosteric replacement (1), homology (2), and derivatization (3) of the 4-aminophenol moiety in AM404 and tested them against CB1, CB 2, and FAAH. We found affinities toward both cannabinoid receptors equal to or greater than that of AM404. Shortening the acyl chain from C 20 to C2 led to three new paracetamol analogues: N-(1H-indazol-5-yl)acetamide (5), N-(4-hydroxybenzyl)acetamide (6), and N-(4-hydroxy-3-methoxyphenyl)acetamide (7). Again, 5, 6, and 7 were tested against CB1, CB2, and FAAH without significant activity. However, 5 and 7 behaved like inhibitors of cyclooxygenases in whole blood assays. Finally, 5 (50 mg/kg) and 6 (275 mg/kg) displayed analgesic activities comparable to paracetamol (200 mg/kg) in the mouse formalin test.
- Sinning, Christian,Watzer, Bernhard,Coste, Ovidiu,Nüsing, Rolf M.,Ott, Ingo,Ligresti, Alessia,Di Marzo, Vincenzo,Imming, Peter
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supporting information; experimental part
p. 7800 - 7805
(2009/12/07)
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- Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand
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Several analogs of an endogenous cannabimimetic, arachidonylethanolamide (anandamide), were synthesized to study the structural requirements of the ethanolamide head group. CB1 receptor affinities of the analogs were evaluated by a standard receptor bindi
- Khanolkar, Atmaram D.,Abadji, Vasiliki,Lin, Sonyuan,Hill, W. Adam G.,Taha, Gihan,Abouzid, Khaled,Meng, Zhaoxing,Fan, Pusheng,Makriyannis, Alexandros
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p. 4515 - 4519
(2007/10/03)
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